Cell differentiation inducing amide derivatives, their production and use

ABSTRACT

The present invention provides a compound represented by the formula:                    
     wherein R 1  is an amino group which may be substituted; R 2  is a hydrogen atom or a lower alkyl group which may be substituted; X is a methyne group which may be substituted or N(O)m (m is 0 or 1); a ring A is a homo- or hetero-cycle which is substituted by a halogen atom, lower alkyl, lower alkoxy or lower alkylenedioxy; and a ring B is a homo- or hetero-cycle which may be substituted; or a salt thereof, which exhibits excellent cell differentiation-inducing action and cell differentiation-inducing factor action-enhancing action, and is useful in the treatment and prevention of various nerve diseases or bone/joint diseases.

This application is the National Stage of International PatentApplication Ser. No. PCT/JP98/01871, filed Apr. 23, 1998.

TECHNICAL FIELD

The present invention relates to amide derivatives exhibiting excellentcell differentiation-inducing actions or cell differentiation-inducingaction-enhancing actions such as bone morphogenetic protein (BMP) actionor BMP-enhancing action or neurotrophic factor (NTF) actions (e.g.,nerve growth factor (NGF) action, brain-derived neurotrophic factor(BDNF) action, neurotrophin-3 (NT-3) action and glial cell line-derivedneurotrophic factor (GDNF) action) or NTF-enhancing action, a method oftheir production and a pharmaceutical composition containing them.

BACKGROUND ART

Bone morphogenetic protein (BMP), isolated from demineralized bone, isthe only group of protein factors known to be capable of ectopic boneinduction. It is therefore useful as an osteogenesis promoter in bonefracture healing, bone reconstruction etc. (A. E. Wang, Trends inBiotechnology, Vol. 11, pp. 379-383 (1993)).

To date, a number of such substances with BMP action-enhancing activityhave been reported, i.e., retinoic acid, vitamin D3, estrogen andglucocorticoid (V. Rosen & R. S. Thies, Trends in Genetics, Vol. 8, pp.97-102 (1992); Y. Takuwa et al., Biochemical and Biophysical ResearchCommunications, Vol. 174, pp. 96-101 (1991)).

Also, because BMP directly promotes osteoblast differentiation, it isassumed to play a role as a coupling factor in bone remodelling, and isthought to be closely involved in bone metabolism. Also, it has beenreported that the BMP content in bone substrate in aged animals has beenconsiderably decreased (M. L. Urist, Bone and Mineral Research, Vol. 6(ed. by W. A. Peck), pp. 57-112, Elsevier, 1989), suggesting that BMP isprofoundly involved in the maintenance of bone mass. This suggests thatBMP is promising as a therapeutic drug for various bone diseases such asosteoporosis. However, because BMP is normally present in trace amountsin living body so that its supply is limited, and because BMP is aprotein so that a problem arises in its administration, the targetdiseases to which it is applicable are limited.

In addition, BMP has been reported to possess an activity like that ofneurotrophic factors (V. M. Paralkar et al., Journal of Cell Biology,Vol. 119, pp. 1,721-1,728 (1992)). Also, it is known that the BMP geneis strongly expressed in brain tissue (E. Ozkaynak et al., Biochemicaland Biophysical Research Communications, Vol. 179, pp. 116-123 (1991)).Also, BMP has been suggested as playing an important role in neural tubeformation in embryogenesis (K. Basler et al., Cell. Vol. 73, pp. 687-702(1993)).

Neurotrophic factors, a group of proteinous factors playing an importantrole in the survival and functional expression of neurons, include nervegrowth factor (NGF), brain-derived neurotrophic factor (BDNF),neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor(GDNF). NGF promotes the differentiation and maturation of thesympathetic ganglion cells and dorsal root ganglion cells of the neuraltube in the peripheral nervous system (A. M. Davies & R. M. Lindsay,Developmental Biology, Vol. 111, pp. 62-72 (1985); R. Levi-Montalcini,EMBO Journal, Vol. 6, pp. 1,145-1,154 (1987)), and acts on thecholinergic neurons of septa (procephalic basal ganglia) in the centralnervous system (H. Gnahn et al., Developmental Brain Research, Vol. 9,pp. 45-52 (1983); H. Hatanaka & H. Tsukui, Developmental Brain research,Vol. 30, pp. 47-56 (1986); F. Hefti, Journal of Neuroscience, Vol. 6,pp. 2,155-2,162 (1986)). NGF is essential for the maintenance of nervousfunction even after completion of neuron differentiation. BDNF acts onthe dorsal spinal root ganglion cells and nodal ganglion cells in theperipheral nervous system but does not act on sympathetic ganglion cells(R. M. Lindsay & H. Rohrer, Developmental Biology, Vol. 112, pp. 30-48(1985); R. M. Lindsay et al., Developmental Biology, Vol. 112, pp.319-328(1985); A. M. Davies et al., Journal of Neuroscience, Vol. 6, pp.1,897-1,904 (1986)). On the other hand, in the central nervous system,BDNF acts on the cholinergic neurons and GABA (γ-aminobutyricacid)-acting neurons of septa, and the dopaminergic neurons of themesencephalon (R. F. Alderson et al., Neuron, Vol. 5, pp. 297-306(1990); C. Hyman et al., Nature, Vol. 350, pp. 230-232 (1991); B. Knuselet al., Proceedings of the National Academy of Sciences of the UnitedStates of America, Vol. 88, pp. 961-965 (1991)). NT-3 is characterizedby potent action on the sensory neurons derived from the neural plate,although its action overlaps those of NGF and BDNF in the peripheralnervous system (P. Ernfors et al., Proc. Natl. Acad. Sci. USA, Vol. 87,pp. 5,454-5,458 (1990); A. Rosenthal et al., Neuron, Vol. 4, pp. 767-773(1990)). However, there are no known neurons of the central nervoussystem that respond to NT-3.

As a substance exhibiting NGF action, sabeluzole[4-(2-benzothiazolylmethylamino)-α(p-fluorophenoxy)methyl]-1-(piperidine)ethanol] has been reported (New Current, Vol. 4, No. 26, p. 14 (1993)];in addition, SR57746A [Neuroscience, Vol. 55, p. 629 (1993)), T-588(Japanese Patent Unexamined Publication No. 95070/1992) and MS430(Journal of University of Occupational and Environmental Health, Vol.17, p. 131 (1995)) have also been reported to enhance NGF action. Also,as compounds exhibiting NGF secretion-inducing action, steroids,catechols and cytokines have been reported (Experimental Neurology, Vol.124, pp. 36-42 (1993)).

Alzheimer dementia has been characterized by extensive lesion andexfoliation of cerebrial cortical neurons, as well as degeneration andexfoliation of cholinergic neurons of the basal ganglia, including theseptal area; NGF and new neurotrophic factors are considered ascandidates for therapeutic drugs therefor (F. Hefti & W. J. Weiner,Annual Neurology, Vol. 20, pp. 275-281 (1986)). Because theseneurothrophic factors are proteins, however, their application aresubject to limitation.

Also, low-molecular compounds known to promote osteoblast proliferationand differentiation include, for example, ipriflavone (K. Notoya et al.,Journal of Bone and Mineral Research, Vol. 9, pp. 395-400 (1994)) andvitamin K2 (Y. Akedo et al., Biochemical and Biophysical Research, Vol.187, pp. 814-820 (1992)) but these do not possess ectopic bone inductioncapability as does BMP.

Compounds known to exhibit actions like those of neurotrophic factors,such as the extension of neurites and neuron survival, includelactastatin (S. Omura et al., Journal of Antibiotics, Vol. 40, pp.113-117 (1991)), retinoic acid (M. Minana et al., Proceedings of theNational Academy of Science of the USA, Vol. 876, pp. 4335-4339 (1990)),staurosporin (T. B. Shea et al. Journal of Neuroscience Research, Vol.33, pp. 398-407 (1990)), K252a (G. D. Borasio et al., NeuroscienceLetters, Vol. 108, pp. 207-212 (1990)), and MS818 (A. Awaya et al.,Biological and Pharmaceutical Bulletin, Vol. 16, pp. 248-253 (1993)).

(1) A naphthalenecarboxamide represented by the formula:

wherein Ar¹ represents allylene-(R⁸)₂ (R⁸: a hydrogen atom, halogen,lower alkyl, hydroxy, lower alkoxy etc.); Ar² represents aryl-(R⁹)₂ (R⁹:a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy etc.); R¹represents a hydrogen atom, lower alkyl, hydroxy or lower alkoxy; R²represents a hydrogen atoms, lower alkyl or a group which forms ═O incooperation with R¹; R³ represents a hydrogen atom, halogen, loweralkyl, hydroxy, lower alkoxy or the like; R⁴ represents a hydrogen atomor lower alkyl; R⁷ represents a hydrogen atom, halogen, lower alkyl,hydroxy, lower alkoxy or the like; each of R¹⁰ and R¹¹ represents ahydrogen atom, halogen, lower alkyl, hydroxy, a lower alkoxy, CON(R¹⁶)₂(R¹⁶ represents a hydrogen atom, lower alkyl or OR¹³ (R¹³ is a hydrogenatom or lower alkyl)) or the like; is disclosed in U.S. Pat. No.5,308,852;

(2) a compound represented by the formula:

wherein R represents a hydrogen atom, acetyl or methyl, is disclosed inJapanese Patent Unexamined Publication No. 153625/1991; and

(3) a compound represented by the formula:

is disclosed in Heterocycles, Vol. 38, pp. 103-111 (1994), etc.

However, the publications disclosing the carboxamide compounds (1) to(3) above give no description of cell differentiation-inducing action orcell differentiation-inducing factor action-enhancing action, bonemorphogenetic protein (BMP) action or BMP action-enhancing action,neurotrophic factor (NTF) action or NTF action-enhancing action.

In view of the above aspects, any compounds which enhance BMP action,for example, would enhance the action of BMP present in vivo oradministered to the living body and would be useful as a therapeuticdrug for bond diseases as described above. However, conventionalsubstances, when administered in vivo, are known to promote boneresorption and have side effects such as hypercalcemia and ovariancancer onset, and are not always appropriate for use as therapeuticdrugs for bone diseases.

On the other hand, any compounds which enhance the action of NGF, forexample, would enhance the action of NGF present in vivo or administeredto the living body and would be useful as a therapeutic drug fordementia and peripheral neuropathy; however, their action mechanismremains to be clarified; clinical studies have demonstrated some suchsubstances have side effects such as headache, dizziness and fatigue,others remain to be proven effective in humans, others possessinsufficient activity, others possess nervous toxicity, and othersexhibit pharmaceutically undesirable actions such as immunity reduction,hypercalcemia and boner resorption promotion, so they are unsatisfactoryfor practical application.

Moreover, because cell differentiation induction factors represented byBMP or neurotrophic factors are proteins, their administration to theliving body are subject to limitation. Compounds which enhance theaction of cell differentiation induction factors present in vivo oradministered to the living body are therefore preferably of lowmolecular weight.

Also, even if the compound itself possesses cell differentiationinduction factor action, as exemplified by BMP and neurotrophic factors,provided that is of low molecular weight, it is believed to serveadvantageously over BMP and neurotrophic factors in terms ofadministration to the living body, and other aspects, as an osteogenesispromoter in bone fracture healing and bone reconstruction, and as atherapeutic drug for dementia and peripheral neuropathy.

In other words, conventional compounds that act like neurothrophicfactors, as well as enhance their action, have not been proven to beeffective in humans, and other compounds are unsatisfactory forpractical application in terms of activity potency, toxicity, etc.

There is therefore strong demand for the development of compoundsdiffering from the above-described known substances, possessionexcellent BMP action or neurotrophic factor action or enhancing suchaction, and serving well as a pharmaceutical.

Against this technical background, the present inventors made extensiveinvestigation, and for the firs time succeeded in creating a compoundcharacterized by a unique chemical structure with a carbamoyl group—COR¹ which may be substituted, and represented by the formula:

wherein R¹ is an amino group which may be substituted; R² is a hydrogenatom or a lower alkyl group which may be substituted; X is a methinegroup which may be substituted or N(O)m (m is 0 or 1); a ring a is ahomo- or hetero-cycle which is substituted by a halogen atom, loweralkyl, lower alkoxy or lower alkylenedioxy group; and a ring B is ahomo- or hetero-cycle which may be substituted; or a salt thereof, andfound that this compound, represented by formula (I), or a salt thereofunexpectedly exhibits BMP or neurotrophic factor action, specificallyenhances the actions of BMP and neurotrophic factors, such as osteoblastand neuron differentiation and neuron survival, and is a low-molecularcompound useful as an agent for inducing a cell differentiation orenhancing an action of induction factor of cell differentiation etc.,and is fully satisfactory as a pharmaceutical. The present inventorsmade further investigation based on this finding, and developed thepresent invention.

DISCLOSURE OF INVENTION

The present invention provides:

(1) A compound represented by the formula:

wherein R¹ is an amino group which may be substituted; R²is a hydrogenatom or a lower alkyl group which may be substituted; X is a methynegroup which may be substituted or N(O)m (m is 0 or 1); a ring A is ahomo- or hetero-cycle which is substituted by a halogen atom, loweralkyl, lower alkoxy or lower alkylenedioxy; and a ring B is a homo- orhetero-cycle which may be substituted; or a salt thereof,

(2) The compound as defined in (1) wherein R¹ is

(I) an amino group which may be substituted by

(a) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclicamino, (xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xvii) C₆₋₁₀aryloxy,

(b) a hydroxy group which may be substituted by a C₁₋₆ alkyl group, C₂₋₆alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ arylgroup or C₇₋₁₆ aralkyl group, which may be substituted by a groupselected from the group consisting of (i) a halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl,(ix) optionally halogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino,(xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acylamino selected from C₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy, or

(c) an amino group which may be substituted by an acyl group representedby any one of the formula: —(C═O)—R⁷, —SO₂—R⁷, —SO—R⁷, —(C═O)NR⁸R⁷,—(C═O)O—R⁷, —(C═S)O—R⁷ or —(C═S)NR⁸R⁷ wherein R⁷ is (a) hydrogen atom or(b) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclicamino, (xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carbonyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy, and R⁸ is hydrogen atom or a C₁₋₆ alkyl group, or

(II) a group formed by removing a hydrogen atom from a nitrogen atom ofa 5 to 9 membered nitrogen-containing heterocycle which may have 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, other than carbon atoms and one nitrogen atom, and thenitrogen-containing heterocycle may be substituted by a group selectedfrom the group consisting of (i) a halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy; R² is (a) ahydrogen atom or (b) a C₁₋₆ alkyl group which may be substituted by agroup selected from that consisting of (i) a halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy; X is N(O)m(m is 0 or 1) or CR⁶′ wherein R⁶′ is

(a) a hydrogen atom,

(b) a halogen atom,

(c) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclicamino, (xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy or

(d) —OR⁶″ wherein R⁶″ is (a′) a hydrogen atom or (b′) a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group which may be substituted by agroup selected from the group consisting of (i) a halogen atom, (ii)C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenatedC₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy; the ring ais a 3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom other than carbon atoms, and the 3 to 10membered cyclic hydrocarbon or 5 to 9 membered heterocycle issubstituted by a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₃alkylenedioxy, and adjacent substituents of the ring A may combine witheach other and form a 3 to 10 membered cyclic hydrocarbon; and

the ring B is a 3 to 10 membered cyclic hydrocarbon or 5 to 9 memberedheterocycle containing 1 to 4 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom other than carbon atoms, and the3 to 10 membered cyclic hydrocarbon or 5 to 9 membered heterocycle maybe substituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclicamino, (xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl., (xviii) carbonyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy,

(3) the compound as defined in (1) wherein R¹ is a group represented bythe formula:

wherein R³ and R⁴ is the same or different and are independently ahydrogen atom, a hydroxy group which may be substituted, a lower alkylgroup which may be substituted, an acyl group, an aryl group which maybe substituted or an aralkyl group which may be substituted, or R³ andR⁴ may combine with an adjacent nitrogen atom and form anitrogen-containing heterocyclic group which may be substituted,

(4)The compound as defined in (3) wherein R³ and R⁴ is the same ordifferent and are independently a hydrogen atom, a hydroxy group whichmay be substituted, a lower alkyl group which may be substituted or anacyl group, or R³ and R⁴may combine with an adjacent nitrogen atom andform a nitrogen-containing heterocyclic group which may be substituted,

(5) The compound as defined in (3) wherein R³ and R⁴ is the same ordifferent and are independently a hydrogen atom or a lower alkyl groupwhich may be substituted,

(6) The compound as defined in (3) wherein R³ is a hydrogen atom or aC₁₋₆ alkyl group, and R⁴ is (i) a hydrogen atom or (ii) a C₁₋₆ alkylgroup which may be substituted by a group selected from the groupconsisting of hydroxy, carboxyl, C₁₋₆ alkoxy-carbonyl, amino and mono-or di-C₁₋₆ alkyl amino, (iii) a C₆₋₁₄ aryl group which may besubstituted by C₁₋₆ alkoxy or (iv) a C₇₋₁₆ aralkyl group which may besubstituted by C₁₋₆ alkoxy or C₁₋₆ acylamino, or R³ and R⁴ combine withan adjacent nitrogen atom and form a 5 to 8 membered nitrogen-containingheterocyclic group which may be substituted by C₇₋₁₆ aralkyl,

(7) The compound as defined in (1) wherein R² is a hydrogen atom or alower alkyl group which may be substituted,

(8) The compound as defined in (1) wherein R² is (i) a hydrogen atom or(ii) a C₁₋₆ alkyl group which may be substituted by a group selectedfrom the group consisting of hydroxy, carbamoyl optionally having C₁₋₆alkyl and amino optionally having C₁₋₆ alkyl,

(9) The compound as defined in (1) wherein X is a methyne group whichmay be substituted,

(10) The compound as defined in (1) wherein X is a methyne group whichmay be substituted by C₁₋₆ alkyl,

(11) The compound as defined in (1) wherein X is N(O)m (m is 0 or 1),

(12) The compound as defined in (1) wherein X is N,

(13) The compound as defined in (1) wherein the ring A is a benzene ringwhich is substituted by a halogen atom, lower alkyl, lower alkoxy orlower alkylenedioxy,

(14) the compound as defined in (1) wherein the ring A is a C₆₋₁₂aromatic hydrocarbon ring which is substituted by a group selected fromthe group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy and C₁₋₃alkylenedioxy,

(15) The compound as defined in (1) wherein the ring B is a benzene ringwhich may be substituted,

(16) The compound as defined in (1) wherein the ring B is (i) a C₆₋₁₂aromatic hydrocarbon ring which may be substituted by a group selectedfrom the group consisting of a halogen atom, optionally halogenated C₁₋₆alkyl, optionally halogenated C₁₋₆ alkoxy and C₁₋₃ alkylenedioxy or,(ii) a 5 to 8 membered heterocycle containing 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom otherthan carbon atoms, and the 5 to 8 membered heterocycle may besubstituted by C₁₋₆ alkyl,

(17) The compound as defined in (1) wherein R¹ is a group represented bythe formula:

wherein

R³′ is a hydrogen atom or C₁₋₆ alkyl group, and

R⁴′ is (i) a hydrogen tom, (ii) a C₁₋₆ alkyl group which may besubstituted by a group selected from the group consisting of hydroxy,carboxyl, C₁₋₆ alkoxy-carbonyl, amino and mono- or di-C₁₋₆ alkylamino,(iii) a C₆₋₁₄ aryl group which may be substituted by C₁₋₆ alkoxy or (iv)a C₇₋₁₆ aralkyl group which may be substituted by C₁₋₆ alkoxy or C₁₋₆acylamino, or R³′ and R⁴′ may combine with an adjacent nitrogen atom andform a 5 to 8 membered nitrogen-containing heterocyclic group which maybe substituted by C₇₋₁₆ aralkyl;

R² is (i) a hydrogen atom or (ii) a C₁₋₆ alkyl group which may besubstituted by a group selected from the group consisting of hydroxy,carbamoyl optionally have C₁₋₆ alkyl and amino optionally having C₁₋₆alkyl;

X is a methyne group which may be sustituted by C₁₋₆ alkyl or N(O)m (mis 0 or 1);

the ring A is C₆₋₁₂ aromatic hydrocarbon ring which is substituted by agroup selected from the group consisting of a halogen atom, C₁₋₆ alkyl,C₁₋₆ alkoxy and C₁₋₃ alkylenedioxy; and

the ring B is (i) a C₆₋₁₂ aromatic hydrocarbon ring which may besubstituted by a group selected from the group consisting of a halogenatom, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆alkoxy and C₁₋₃ alkylenedioxy or (ii) a 5 to 8 membered heterocyclecontaining 1 to 3 hetero atoms selected from a nitrogen atom, an oxygena tom and a sulfur atom other than carbon atoms, and the 5 to 8 memberedheterocycle may be substituted by C₁₋₆ alkyl,

(18) The company as defined in (1) wherein R¹ is a group represented bythe formula:

wherein R³″ is a hydrogen atom and R⁴″ is a hydrogen atom or C₇₋₁₆aralkyl group which may be substituted by C₁₋₆ alkoxy; R² is a hydrogenatom or C₁₋₆ alkyl group which may be substituted by hydroxy; X is amethyne group or N; the ring A is a C₆₋₁₂ aromatic hydrocarbon ringwhich is substituted by C₁₋₆ alkoxy or C₁₋₃ alkylenedioxy; and the ringB is a C₆₋₁₂ aromatic hydrocarbon ring which may be substituted by agroup selected from the group consisting of a halogen atom, C₁₋₆ alkoxyand C₁₋₃ alkylenedioxy,

(19)N-methyl-9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-6-carboxamide or a salt thereof,

(20) N-methyl-8-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-naphtho[2,3-d]-1,3-benzodioxole-6-carboxamide or a salt thereof,

(21) 9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,

(22) N-methyl-4-(1,3-benzodioxole-5-yl)-6,7-diethoxy-3-hydroxymethyl-naphthalene-2-carboxamideor a salt thereof,

(23) 9-(4-methoxyphenyl)-N-[(4-methoxyphenyl)menthyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,

(24) 9-(1,3-benzodioxole-5-yl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,

(25)9-(4-fluorophenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamideor a salt thereof,

(26) A method for producing a compound represented by the formula:

wherein R¹¹ is a lower alkyl group which may be substituted and othersymbols are same as defined in (1), or a salt thereof which comprisessubjecting a compound represented by the formula:

wherein each symbol is a same as defined in (1), or a salt thereof to afunctional group-converting reaction or/and a carbon-adding reaction,

(27) A method for producing the compound as defined in (1) or a esterthereof, or a salt thereof which comprises subjecting a compoundrepresented by the formula:

wherein each symbol is same as defined in (1), or a salt thereof to anamidating reaction, and if desired followed by a acylating reaction,

(28) A pharmaceutical composition which comprises the compound asdefined in (1) or a salt thereof,

(29) An agent for inducing a cell differentiation or enhancing an actionof induction factor of cell differentiation which comprises a compoundrepresented by the formula:

wherein a ring A′ is a homo- or hetero-cycle which may be substitutedand other symbols are same as defined in (1),

(30) The agent as defined in (29) wherein the ring A′ is (a) 3 to 10membered cyclic hydrocarbon or (b) a 5 to 9 membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom other than carbon atoms, and the 3 to 10membered cyclic hydrocarbon or 5 to 9 membered heterocycle may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆alkynyl, (viii) C₃₋₆cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkylamino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclicamino, *xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoly,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi)c₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy; or adjacent substituents of the ring A′ may combine with eachother and form (a) a 3 to 10 membered cyclic hydrocarbon, (b) a 3 to 9membered aromatic heterocycle containing 1 to 4 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom other than carbonatoms or (c) a 5 to 9 non-aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atomother than carbon atoms,

(31) The agent as defined in (28) which is an agent for treating orpreventing nerve diseases or bone/joint diseases,

(32) The agent as defined in (31) wherein the nerve disease is a diseasebased on nerve degeneration in cerebrovascular dementia, senile dementiaor Alzheimer's disease; amyotrophic lateral aclerosis; diabeticperipheral neuropathy; or Parkinson disease,

(33) A method for treating or preventing nerve diseases or bone/jointdiseases which comprises administering an effective amount of thecompound as defined (1) or a salt thereof to mammals,

(34) The method as defined in (33) wherein the nerve disease is adisease based on nerve degeneration in cerebrovascular dementia, seniledementia or Alzheimer's disease; amyotrophic lateral aclerosis; diabeticperipheral neurotrophic lateral aclerosis; diabetic peripheralneuropathy; or Parkinson disease,

(35) Use of the compound as defined in (1) or a salt thereof forpreparing an agent for treating or preventing nerve disease orbone/joint disease, and

(36) The use of defined in (35) wherein the nerve disease is a diseasebased on nerve degeneration in cerebrovascular dementia, senile dementiaor Alzheimer's disease; amyotrophic lateral aclerosis; diabeticperipheral neurotrophic laterial aclerosis; diabetic peripheralneuropathy; or Parkinson disease.

DETAILED DESCRIPTION

In the above mentioned formula, the ring A represents a homo- orhetero-cycle which is substituted by a halogen atom, lower alkyl, loweralkoxy or lower alkylenedioxy.

The homo- or hetero-cycle has any (preferably 1 to 5, more preferably 1to 3) substituents as mentioned above at a position where it can besubstituted. When a number of substituents are more than 2, eachsubstituent may be same or different, and adjacent substituents maycombine each other and form a ring.

When adjacent substituents of the ring A combine with each other andform a ring, examples of the ring are 3 to 10 membered cyclichydrocarbon, preferably a 5 to 6 membered cyclic hydrocarbon. Specificexamples of the ring are benzene, C₃₋₁₀ cycloalkene (e.g. cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C₃₋₁₀cycloalkane (e.g. cyclobutane, cyclopentane, cyclohexane, cyclopheptane,cyclooctane, etc.), and so on. Preferable examples of the cycle are a 5to 6 membered homocycle such as benzene, cyclopentane, cyclohexane, andmore prefereable examples are a benzene ring.

When adjacent substituents of the ring A combine with each other andform a condensed ring with the ring A, examples of the condensed ringare naphtharene, and so on.

In the above mentioned formula, the homocycle represented by the ring Ameans a cyclic hydrocarbon consisting of carbon atoms. Examples of thecyclic hydrocarbon are a 3 to 10 membered cyclic hydrocarbon, preferablya 5 to 6 membered cyclic hydrocarbon. Specific examples of the homocycleare benzene, C₃₋₁₀ cycloalkene (e.g cyclobutene, cyclopentene,cyclohexene, cycloheptene, cyclooctene, etc.), C₃₋₁₀ cycloalkane (e.g.cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.)and so on. Preferable examples are 5 to 6 membered homocycle such asbenzene, cyclopentane, cyclohexane, and more preferable examples are abenzene ring and so on.

In the above mentioned formula, examples of the heterocycle representedby the ring A are an aromatic heterocycle or non-aromatic heterocyclecontaining more than 1 (e.g., 1 to 4, preferably 1 to 3) and one or twokinds of hetero atoms selected from a nitrogen atom, a sulfur atom andan oxygen atom other than carbon atoms, and so on.

Examples of the aromatic heterocycle are a 5 to 6 membered aromaticheterocycle containing 1 to 3 hetero atoms selected by a nitrogen atom,an oxygen atom and a sulfur atom other than carbon atoms, such a apyridine, pyrazine, pyrimidine, pyridazine, pyrole, imidazole, pyrazole,triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazolering, and so on. More preferable examples are a 6 memberednitrogen-containing heterocycle such as a pyridine, pyrazine, thiophene,pyrole, thiazole ring and so on. Particularly, a 6-memberednitrogen-containing heterocycle containing 1 or 2 nitrogen atoms otherthan carbon atoms (e.g. pyridine, pyrazine) is preferred.

Examples of the non-aromatic heterocycle are a 5 to 9 memberednon-aromatic heterocycle, preferably a 5 to 6 membered non-aromaticheterocyle, containing 1 to 3 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom other than carbon atoms, and soon.

Specific examples of the non-aromatic heterocycle are atetrahydropirdine, dihydropyridine, tetrahydropyrazine,tetrahydropyrimidine, tetrahydropyridazine, dihydropyrane,dihydropyrole, dihydroimidazole, dihydropyrazole, dihydrothiophene,dihydrofurane, dihydrothiazole, dihydroisothiazole, dihydrooxazole,dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine,hexahydropyridazine, tetrahydropyrane, morphorine, pyrolodine,imidazolidide, pyrazoridine, tetrahydrorthiophene, tetrahydrofurane,tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole,tetrahydroisoxazole ring and so on. Preferable examples are a 6 memberednon-aromatic heterocycle containing 1 to 2 nitrogen atoms such as atetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine,pyperidine, pyperazine ring, and more preferably examples are apyperazine ring and so on.

In the homo- or hetero-cycle which is substituted by a halogen atom,lower alkyl, lower alkoxy or lower alkylenedioxy represented by the ringA,

(i) examples of the halogen atom are fluorine, chlorine, bromine andiodine

(ii) examples of the lower alkyl are a linear or branched C₁₋₆ alkylsuch as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl,tert-buthyl, penthyl, hexyl and so on, preferably methyl,

(iii) examples of the lower alkoxy are a linear or branched C₁₋₆ alkoxysuch as methoxy, ethoxy, propoxy, isopropoxy, buthoxy, isobuthoxy,sec-buthoxy, tert-buthoxy and so on, preferably methoxy,

(iv) examples of the lower alkylenedioxy are a C₁₋₃ alkylenedioxy suchas methylendioxy, ethylendioxy, propylenedioxy and so on, preferably,ethylenedioxy.

Preferable examples of the ring A are a homocycle (preferably, a C₆₋₁₂aromatic hydrocarbon ring) which is substituted by a halogen atom, loweralkyl ( e.g. C₁₋₆ alkyl), lower alkoxy (e.g. C₁₋₆ alkoxy) or loweralkylenedioxy (e.g. C₁₋₃ alkylenedioxy), and more preferable examplesare a benzene ring which is substituted by a halogen atom, C₁₋₆ alkyl,C₁₋₆ alkoxy or C₁₋₆ alkylenedioxy.

In the above mentioned formula, the ring A′ represents a homo- orhetero-cycle which may be substituted.

In the above mentioned formula, examples of the homocycle or heterocyclerepresented by the ring A′ are the homo- or hetero-cycle of the “homo-or hetero-cycle which is substituted by a halogen atom, lower alkyl,lower alkoxy or lower alkylenedioxy” represented by the ring A.

The homo- or hetero-cycle has any (preferably 1 to 5, more preferably 1to 3) substiuents at a position where can be substituted. When a numberof substituents are more than 2, each substituent may be same ordifferent, and adjacent substituents may combine with each other andform a ring.

When adjacent substituents of the ring A combine with each other andform a ring, examples of the ring are

(i) a 3 to 10 membered cyclic hydrocarbon, preferably a 5 to 6 memberedcyclic hydrocarbon,

(ii) a 3 to 9 membered aromatic heterocycle, preferably a 5 or 6membered aromatic heterocycle containing more than 1 (e.g., 1 to 4,preferably 1 to 3) and one or two kinds of hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms,or

(iii) a 5 to 9 membered non-aromatich heterocycle, preferably a 5 or 6membered non-aromatich heterocycle, containing more than 1 (e.g., 1 to4, preferably 1 to 3) and one or two kinds of hetero atoms selected froma nitrogen atom, an oxygen atom and a sulfur atom other than carbonatoms and so on.

Specific examples of the 3 to 10 membered cyclic hydrocarbon in theabove (i) are benzene, C₃₋₁₀ cycloalkene (e.g. cyclobutene,cyclopentene, cyclohexane, cycloheptene, cyclootene, etc.), C₃₋₁₀cycloalkane (e.g. cyclobutane, cyclopetane, cyclohexane, cycloheptane,cyclootane, etc.), and so on. Preferable examples are 5 to 6 homocyclesuch as benzene, cyclopentane, an cyclohexane, and more preferableexamples area benzene ring, and so on.

Examples of the aromatic heterocycle of the above (ii) are a 5 to 9membered, preferably a 5 to 6 membered, aromatic heterocycle containing1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom other than carbon atoms such as a pyridine, pyrazine,pyrimidine, pyridazine, pyrole, imidazole, pyrazole, triazole,thiophene, furan, thiazole, isothiazole, oxazole and isoxazole ring, andso on.

Examples of the non-aromatic heterocycle of the above (iii) area a 5 to9 membered, preferably a 5 to 6 membered, non-aromatic heterocyclecontaining 1 to 3 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom other than carbon atoms and so on. Specificexamples of the non-aromatic heterocycle are a tetrahydropiridine,dihydropyridine, tetrahydropyradine, tetrahydropyrimidine,tetrahydropyridazine, dihydropyrane, dihydropyrole, dihydromidazole,dihydropyrazole, dihydrothiophene, dihydrofurane, dihydrothiazole,dihydroisothiazole, dihydrooxazole, dihydrioisoxanzone, piperidine,piperazine, hezahydropyrimidine, hexahydropyridazine, tetrahydrophyrane,morphorine, pyrrolidine, imidazolidide, pyrazoridine,tetrahydrorthiophene, tetrahydrofurane, tetrahydrothiazole,tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole ring, andso on.

When adjacent substituents of the ring A′ combine with each other andform a condensed ring with the ring A′, examples of the condensed ringare naphtharene, and so on.

In the above mentioned formula, examples of the substituents of thehomo- or hetero-cycle represented by the ring A′ are

(i) a halogen atom (e.g. fluorine, chlorine, bromine, iodine),

(ii) lower alkylendedioxy (e.g. C₁₋₃ alkylenedioxy such asmethylenedioxy, ethylenedioxy),

(iii) nitro,

(iv) cyano,

(v) optionally halogenated lower alkyl,

(vi) optionally halogenated lower alkenyl,

(vii) optionally halogenated lower alkynyl,

(viii) lower cycloalkyl (e.g. C₃₋₆ cycloalkyl such as cyclopropyl,cyclobuthyl, cyclopenthyl, cyclohexyl),

(ix) optionally halogenated lower alkoxy,

(x) optionally halogenated lower alkylthio,

(xi) hydroxy,

(xii) amino,

(xiii) mono-lower alkylamino (e.g. mono-C₁₋₆ alkylamino such asmethylamino, ethylamino, propylamino, isopropylamino, buthylamino),

(xiv) di-lower alkylamino (e.g. di-C₁₋₆ alkyl amino such asdimethylamino, diethylamino, dipropylamino, dibuthylamino),

(xv) 5 or 6 membered cyclic amino (e.g. morpholino, pyperadine-1-yl,pyperidino, pyroridine-1yl,

(xvi) acyl amino

(xvii) lower alkyl-carbonyl (e.g. C₁₋₆ alkyl-carbonyl such as acetyl,propyoyl),

(Xviii) carboxyl,

(xix) lower alkoxy-carbonyl (e.g. C₁₋₆ alkoxy-carbonyl such asmethoxycarbonyl, ethoxycarbonyl, propxycarbonyl, butoxycarbonyl),

(xx) carbamoyl,

(xxi) mono-lower alkyl-carbamoyl (e.g. mono-C₁₋₆ alkyl-carbamoyl such asmethylcarbamoyl, ethylcarbamoyl),

(xxii) di-lower alkyl-carbamoyl (e.g.di-C₁₋₆ alkyl-carbamoyl such asdimethylcarbamoyl, diethylcarbamoyl),

(xxiii) aryl-carbamoyl (e.g. C₆₋₁₀ aryl-carbamoyl such asphenylcarbamoyl, naphtylcarbamoyl),

(xxiv) sulfo,

(xxv) lower alkyl sulfonyl (e.g. C₁₋₆ alkyl sulfonyl such asmethylsulfonyl, ethylsulfonyl),

(xxvi) aryl (e.g. C₆₋₁₀ aryl such as phenyl, naphthyl) or

(xxvii) aryloxy (e.g. C₆₋₁₀ aryloxy such as phenyloxy, naphthyloxy).

Examples of the optionally halogenated lower alkyl are lower alkyl (e.g.C₁₋₆ alkyl such a methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl,sec-buthyl, tert-buthyl, penthyl, hexyl) optionally having 1 to 3halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on.Specific examples of the optionally halogenated lower alkyl are methyl,chloromethyl, difluoremethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2,-trifluoroethyl, propyl, 3,3,3,-trifluoropropyl,isopropyl, buthyl, 4,4,4-trifluorobuthyl, isobuthyl, sec-buthyl,tert-buthyl, penthyl, isopenthyl, neopenthyl, 5,5,5- trifluropenthyl,hexyl, 6,6,6-trifluorohexyl and so on.

Examples of the optionally halogented lower alkenyl are lower alkenyl(e.g. C₂₋₆ alkenyl such as vinyl, propenyl, isopropenyl, 2-butene-1-yl,4-penthene-1-yl, 5-hexene-1-yl) optionally having 1 to 3 halogen atoms(e.g. fluorine, chlorine, bromine, iodine) and so on.

Examples of the optionally halogenated lower alkynyl are lower alkynly(e.g. C₂₋₆ alkynly such as 2-butyne1-yl, 4- pentyne-1-yl, 5-hexyne-1-yl)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine,bromine, iodine) and so on.

Examples of the optionally halogenated lower alkoxy are lower alkoxy(e.g. C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy,n-buthoxy, isobuthoxy, sec-buthoxy, tert-cuthoxy) optionally having 1 to3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and so on.Specific examples of the optionally halogenated lower alkoxy aremethoxy, difluoromethoxy, tirfluoromethoxy, ethoxy,2,2,2-trifluorobuthoxy, n-propoxy, isopropoxy, n-butoxy,4,4,4-trifluorobuthoxy, isobuthoxy, sec-buthoxy, penthyloxy, hexyloxyand so on.

Examples of the optionally halogenated lower alkylthio are loweralkylthio (e.g. C₁₋₆ alkylthio such as methylthio, ethylthio,n-propylthio, isopropylthio, n-buthylthio, isobuthylthio,sec-buthylthio, tert-buthylthio) optionally having 1 to 3 halogen atoms(e.g. fluorine, chlorine, bromine, iodine) and so on. Specific examplesof the optionally halogenated lower alkylthio are methylthio,difluromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, buthylthio, 4,4,4-trifluorobuthylthio, penthylthio,hexylthio and so on.

Examples of the acylamino are —NHCOOR⁵, —NHCOHNR⁵, —NHCOR⁵ or —NHSO₂R⁵wherin R⁵ is a hydrocarbon group.

Examples of the hydrocarbon group represented by R⁵ is a group formed byremoving one hydrogen atom from the hydrocarbon compound and so on.Specific examples are a linear or cyclic hydrocarbon group such as analkyl group, an alkenyl group, an alkynyl group a cycloalkyl group, anaryl group an ararkyl group and so on. Of them, a C₁₋₁₆ chain ( linearor branched) or cyclic hydrocarbon group, and more preferable examplesare

(a) alkyl group, preferably lower alkyl group (e.g. C₁₋₆ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, buthyl, isobuthyl, sec-buthyl,tert-buthyl, penthyl, hexyl),

(b) alkenyl group, preferably lower alkenyl group (e.g. C₂₋₆ alkenylsuch as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl),

(c) alkynly gorup, preferably lower alkynly (e.g. C₂₋₆ alkynly such aspropalgyl, ethynyl, butynyl, 1-hexynyl),

(d) cycloalkyl group, preferably lower cycloalkyl (e.g. C₃₋₆ cycloalkylsuch as cyclopropyl, cyclobuthyl, cyclopenthyl, cyclohexyl which maycondense with a benzene ring optionally having 1 to 3 lowe alkoxys (e.g.C₁₋₆ alkoxy such as methoxy)).

(e) an aryl group (e.g. C₆₋₁₄ aryl group such as phenyl, tryl, xylyl,biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-antryl,2-antryl, 3-antryl, 1-phenantryl, 2-phenantryl, 3-phenantryl,4-phenantryl or 9-phenantryl, preferably phenyl),

(f) an ararkly group (e.g. C₇₋₁₆ aralkyl group such as benzyl, phenetyl,diphenylmethyl, 1-napthylmethyl, 2-naphtylmethyl, 2phenylethyl,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,4-phenylbuthyl or 5phenylpenthyl, preferably benzyl).

In the above mentioned formula, preferable examples of the substituentsof the “homo- or hetero-cycle represented by the A′ are a halogen atom,an optionally halogenated lower alkyl group (preferably methyl), anoptionally halogenated lower alkoxy group (preferably methoxy), a loweralkylenedioxy group (preferably methylendedioxy) or a hydroxy group, andmore preferable examples are a lower alkoxy (preferably methoxy), alower alkylenedixoy group (preferably methylenedioxy) and so on.

Preferable examples of the ring A′ are a homocycle which may besubstituted, and more preferable examples are a benzene ring which maybe substituted and so on. Specifically, the above mentioned preferableexamples of the ring A are also used as preferable examples of the ringA.

In the above mentioned formula, Examples of the homocycle andheterocycle represented by the ring B are the homocycle and heterocycleof the “homo- or hetero-cycle which may be substituted by a halogenatom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxygroup” represented by the ring A.

In the above mentioned formula, Examples of the substituents of the“homo- or hetero-cycle which may be substituted ” represented by thering B are the same those of the substituents of the “homo- orhetero-cycle which may be substituted” represented by the ring A′.

Preferable examples of the substituents of the “homo- or hetero-cyclewhich may be substituted” represented by the ring B are (i) a halogenatom (e.g. fluorine, chlorine, bromine, iodine, etc.), (ii) a loweralkylenedioxy group (e.g. C₁₋₃ alkylenedioxy such s methylenedioxy andethylenedioxy, etc), (iii) an optionally halogenated lower alkyl group(e.g. optionally halogenated C₁₋₆ alkyl such as methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bbromoethyl,2,2,2-trifluroethyl, propyl, 3,3,3-triflluropropyl, isopropyl, buthyl,4,4,4-triflurobuthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl,isopenthyl, neopenthyl, 5,5,5trifluoropenthyl, hexyl,6,6,6-trifluorhexyl and so on, preferably methyl and trifluoromethyl),(iv) an optionally halogenated lower alkoxy (e.g. Optionally halogenatedC₁₋₆ alkoxy such as methoxy, difluoromethoxy, trifluromethoxy, ethoxy,2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-buthoxy,4,4,4-triflurobutoxy, isobuthoxy, sec-buthoxy, penthyloxy, hexyloxy andso on, preferably methoxy), and so on.

Preferable examples of the ring B are a benzene ring which may besubstituted. More preferable examples are (i) a C₆₋₁₂ aromatichydrocarbon ring (preferably, a benzene ring) which may be substitutedby a group selected from the group consisting of a halogen atom,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxyand C₁₋₃ alkylenedioxy or (ii) a 5 to 8 membered heterocycle containing1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom other than carbon atoms and the 5 to 8 membered heterocyclemay be substituted by C₁₋₆ alkyl, and so on.

In the above mentioned formula, X represents a methyne group which maybe substituted or N(O)m (M is 0 or 1).

In the above mentioned formula examples of the “methyne group which maybe substituted ” represented by X are CR⁶ wherein R⁶ is a hydrogen atom,(e.g. fluorine, chlorine, bromine, iodoine), a hydrocarbon group whichmay be substituted or a hydroxy group which may be substituted, and soon.

Examples of the hydrocarbon group represented by R⁶ are the hydrocarbongroup represented by the above mentioned R⁵, and more preferableexamples are a lower alkyl group such as methyl, ethyl, propyl,isopropyl, buthyl, isobuthyl, sec-buthyl, penthyl, hexyl and so on.

Examples of the substituents of the hydrocarbon group represented by R⁶are the substituents of the homo- or hetero-cycle represented by theabove mentioned ring A′, and so on.

The hydroxy group which may be substituted represented by R⁶ is (i) ahydroxy group or (ii) a hydroxy group having one group such as the abovementioned hydrocarbon group which may have substituents instead of ahydrogen atom of the hydroxy group. Specifically, the above mentioned—OR⁶″, etc. are used, and preferable examples are a hydroxy group or ahydroxy group having one group such as a lower alkyl group which may besubstituted. Examples of the lower alkyl group are a linear or branchedC₁₋₆ alkyl group (e.g. methyl, ethyl, propyl, isopropyl, buthyl,isobuthyl, sec-buthyl, tert-buthyl, penthyl, hexyl, etc.), and so on.Examples of the substituents of the lower alkyl group are thesubstituents of the homo- or hetero-cycle represented by the abovementioned ring A′.

Preferable examples of X are a methyne group which may be substituted byC₁₋₆ alkyl or N, and more preferable examples are CH, C—CH₃, N and soon.

In the above mentioned formula, R¹ represents an amino group which maybe substituted. Examples of the substituents of the amino group are ahydrocarbon group which may be substituted, a hydroxy group which may besubstituted, an acyl group and so on. And, the amino group which may besubstituted includes a nitrogen-containing heterocyclic group which hasa binding site on a ring-component nitrogen atom, and thenitrogen-containing heterocyclic group may have substituents.

Examples of the hydrocarbon group of the “hydrocarbon group which may besubstituted” are the hydrocarbon goroup of the “homo- or hetero-cyclewhich may be substituted” represented by the above mentioned R⁵ and soon.

Exampales of the substituents of the hydrocarbon group are thesubstituents of the homo- or hetero-cycle represented by the abovementioned ring A′.

Examples of the hydroxy group which may be substituted are the “hydroxygroup which may be substituted” represented by the above mentioned R⁶,and so on.

Examples of the acyl group are —(C═O)—R⁷, —SO₂—R⁷, —SO—R⁷, —(C═O)NR⁸R⁷,—(C═O)O—R⁷, —(C═S)O—R⁷ or —(C═S)NR⁸R⁷ wherein R⁷ is a hydrogen atom or ahydrocarbon group which may be substituted and R⁸ is a hydrogen atom ora lower alkyl group (e.g. a C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, buthyl, isobuthyl, tert-buthyl, penthyl, hexyl and soon, preferably a C₁₋₃ alkyl such as methyl, ethyl, propyl, isopropyl andso on). Of them, —(C═O)—R⁷, —SO₂—R⁷, —SO—R⁷, —(C═O)NR⁸R⁷, —(C═O)O—R⁷ arepreferred, and —(C═O)—R⁷ is more preferred.

Examples of the hydrocarbon group represented by R⁷ is a group formed byremoving one hydrogen from atom from the hydrocarbon compound. Specificexamples are chained (linear or branched) or cyclic hydrocarbon groupsuch as an alkyl group, an alkenyl group, an alkynyl group, a cycloalkylgroup, an aryl group, an ararkyl group and so on. Specifically, thehydrocarbon group represented by R⁵, etc. are used. Of them, a C₁₋₁₆linear or cyclic hydrocarbon group, etc. are preferred and a lower(C₁₋₆) alkyl group, etc. are more preferred.

Examples of the substituents of the hydrocarbon group represented by R⁷are the substituents of the “homo- or hetero-cycle which may besubstituted” represented by the ring A′, and so on.

Examples of the nitrogen-containing heterocyclic group represented byR¹, are a group formed by removing a hydrogen atom from a nitrogen atomof a 5 to 9 membered nitrogen-containing heterocyclic which may have 1to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom other than carbon atoms and one nitrogen atom, and so on.

Specifically,

are preferably used.

Examples of the substituents of the nitrogen-containing heterocyclicgroup are the substituents of the homo- or hetero-cycle which may besubstituted represented by the above mentioned ring A′.

Preferable examples of the amino group which may be substitutedrepresented by R¹ are a group represented by the formula:

wherein R³ and R⁴ is the same or different and are independently ahydrogen atom, a hydroxy group which may be substituted, a lower alkylgroup which may be substituted, or acyl group, an aryl group which maybe substituted or an aralkyl group which may be substituted, or R³ andR⁴ may combine with an adjacent nitrogen atom and form anitrogen-containing heterocyclic group which may be substituted, and soon. Of them, a group wherein R³ and R⁴ is the same or different and areindependently a hydrogen atom, a hydroxy group which may be substituted,a lower alkyl group which may be substituted or an acyl group, or R³ andR⁴ may combine with an adjacent nitrogen atom and form anitrogen-containing heterocyclic group which may be substituted, etc.are preferred.

Examples of the hydroxy group which may be substituted represented by R³and R⁴ are the hydroxy group which may be substituted represented by R⁶,etc.

Examples of the lower alkyl group represented by R³ and R⁴ are a linearor branched C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl and hexyl. Examplesof the substituents of the lower alkyl group are the substituents of thehomo- or hetero-cycle which may be substituted represented by the abovementioned ring A′.

Examples of the acyl group represented by R³ and R⁴ are the abovementioned acyl group which is the substituents of the amino group whichmay be substituted represented by R¹.

Examples of the nitrogen-containing heterocyclic group formed by R³, R⁴and the adjacent nitrogen atom are a group formed by removing a hydrogenatom from a nitrogen atom of a 5 to 9 membered nitrogen-containingheterocyclic which may have 1 to 3 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom other than carbon atoms and onenitrogen atom, and so on.

Specifically,

are preferably used.

Examples of the substituents of the nitrogen-containing heterocyclicgroup are the substituents of the “homo- or hetero-cycle which may besubstituted” represented by the above mentioned ring A′, and so on.

Preferable examples of R³ to R⁴ are the same or different and areindependently a hydrogen atom or a lower alkyl group which may besubstituted, and so on.

Particularly, R³ is a hydrogen atom or a C₁₋₆ alkyl group, and R⁴ is (i)a hydrogen atom or (ii) a C₁₋₆ alkyl group which may be substituted by agroup selected from the group consisting of hydroxy, carboxyl, C₁₋₆alkoxy-carbonyl, amino and mono- or di-C₁₋₆ alkyl amino, (iii) a C₆₋₁₄aryl group which may be substituted by C₁₋₆ alkoxy or (iv) a C₇₋₁₆aralkyl group which may be substituted by C₁₋₆ alkoxy or C₁₋₆ acylamino,or R³ and R⁴ may combine with an adjacent nitrogen atom and form a 5 to8 membered nitrogen-containing heterocyclic group which may besubstituted by C₇₋₁₆ aralkyl (e.g., benzyl).

In the above mentioned formula, R² represents a hydrogen atom or a loweralkyl group which may be substituted.

Examples of the lower alkyl group represented by R² are a linear orbranched C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,buthyl, isobuthyl, sec-buthyl, tert-buthyl, penthyl and hexyl. Examplesof the substituents of the lower alkyl group represented by R² are thesubstituents of the “homo- or hetero-cycle which may have substituents”represented by the above mentioned ring A′, and a hydroxy group isparticularly preferred.

Preferable examples of R² are (i) a hydrogen atom or (ii) a C₁₋₆ alkylgroup which may be substituted by a group selected from the groupconsisting of hydroxy, carbamoyl optionally having C₁₋₆ alkyl and aminooptionally having C₁₋₆ alkyl, and more preferable examples are ahydrogen atom, a C₁₋₆ alkyl group which may be substituted by hydroxy,and so on.

Preferable examples of the compound (I) or (II) are compounds wherein R¹is a group represented by the formula:

wherein R³ is a hydrogen atom or a C₁₋₆ alkyl group, and R⁴′ is (i) ahydrogen atom, (ii) a C₁₋₆ alkyl group which may be substituted by agroup selected from the group consisting of hydroxy, carboxyl, C₁₋₆alkoxy-carbonyl, amino and mono- or di-C₁₋₆ alkylamino, (iii) a C₆₋₁₄aryl (e.g., phenyl) group which may be substituted by C₁₋₆ alkoxy or(iv) a C₇₋₁₆ aralkyl group (e.g., benzyl) which may be substituted byC₁₋₆ alkoxy or C₁₋₆ acylamino, or R³′ and R⁴′ may combine with anadjacent nitrogen atom and form a 5 to 8 membered nitrogen-containingheterocyclic group which may be substituted by C₇₋₁₆ aralkyl (e.g.,benzyl); R² is (i) a hydrogen atom or (ii) a C₁₋₆ alkyl group which maybe substituted selected from the group consisting of hydroxy, carbamoyloptionally having C₁₋₆ alkyl and amino optionally having C₁₋₆ alkyl; Xis a methyne group which may be substituted by C₁₋₆ alkyl or N(O)m (m is0 or 1); the ring A is a C₆₋₁₂ aromatic hydrocarbon ring (e.g., abenzene ring) which is substituted by a group selected from the groupconsisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy and C₁₋₃alkylenedioxy; and the ring B is (i) a C₆₋₁₂ aromatic hydrocarbon ring(e.g., a benzyne ring) which may be substituted by a group selected fromthe group consisting of a halogen atom, optionally halogenated C₁₋₆alkyl, optionally halogenated C₁₋₆ alkoxy and C₁₋₃ alkylenedioxy or (ii)a 5 to 8 membered heterocycle containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom other than carbonatoms and the a 5 to 8 membered heterocycle may be substituted by C₁₋₆alkyl, and so on.

More preferable examples of the compound (I) or (II) are compoundswherein R¹ is a group represented by the formula:

wherein R³″ is a hydrogen atom and R⁴″ is a hydrogen atom or a C₇₋₁₆aralkyl group (e.g., a benzyl group) which may be substituted by C₁₋₆alkoxy; R² is a hydrogen atom or a C₁₋₆ alkyl group which may besubstituted by hydroxy; X is a methyne group or N; the ring A is a C₆₋₁₂aromatic hydrocarbon ring (e.g., a benzene ring) which is substituted byC₁₋₆ alkoxy or C₁₋₃ alkylenedioxy; and the ring B is a C₆₋₁₂ aromatichydrocarbon ring (e.g., a benzene ring) which may be substituted by agroup selected from the group consisting of a halogen atom, C₁₋₆ alkoxyand C₁₋₃ alkylenedioxy, and so on.

More specifically, preferable examples of the compound (I) or (II) are

N-methyl-9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamideor a salt thereof,

N-methyl-8-(1,3-benzodioxole-5-yl)-7-hydroxymethyl-naphtho[2,3-d]-1,3-dioxole-6-carboxamideor a salt thereof,

9-(1,3-benzodioxole-5-yl)-8-hydroxymethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,

N-methyl-4-(1,3-benzodioxole-5-yl)-6,7-diethoxy-3-hydroxymethyl-napthalene-2-carboxamideor a salt thereof,

9-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamideor a salt thereof,

9-(1,3-benzodioxole-5-yl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof,

9-(4-fluorophenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide or a salt thereof, and so on.

The compound (I) or compound (II) of the present invention or a saltthereof (hereinafter simply referred to as the compound (I) or thecompound (II)) can be produced by a variety of methods; representativeexamples are shown in schemes 1 and 2 below.

Note that in the following description of production methods, thestarting material compound and reaction product may form a salt thatdoes not hamper the reaction.

Examples of the “salt that does not hamper the reaction” are the samesalts as those of compound (I) or those of compound (II) below.

Of the compounds included in the compound (I) or the compound (II)wherein X is N(O)m (m represents 0 to 1), those wherein m is 1 or a saltthereof can be produced by a known chemical oxidizing reaction [e.g.,Chemistry of the Heterocyclic N-Oxide, pp. 22-60 (1971), Academic Press,London & New York, or G. Jones ed., “Quinolines part 1,” John Wiley &Sons, Chapter 1, pp. 61-62 (1977)] or a modification thereof at anappropriate stage where the compound occurs as a compound wherein m is 0or a salt thereof or as a production intermediate thereof.

Of the compounds included in the compound (I) or the compound (II), acompound wherein R² is a hydrogen atom and X is a methine group whichmay be substituted, namely a compound (XI), or compound (XI′), can, forexample, be produced by the method shown by scheme 1 below.

With respect to the compounds (IV) to (XI) or the compounds (IV′) to(XI′) in scheme 1 above, E represents a hydrogen atom or a halogen atom(e.g., fluorine, chlorine); R⁹ represents a lower alkyl group (e.g.,methyl, ethyl); the other symbols have the same definitions as thoseshown above.

Of the compounds included in the compound (I), a compound wherein ring Ais a benzene ring which is substituted by a halogen atom, a lower alkylgroup, a lower alkoxy group or a lower alkylenedioxy group, R² is ahydrogen atom, and X is N, can be produced by carrying out a reaction bya commonly known method (E. C. Taylor et al., Journal of OrganicChemistry, Vol. 32, pp. 1899-1900 (1967)), using a compound representedby the formula:

wherein R¹⁰ represents a halogen atom, a lower alkyl group, a loweralkoxy group or a lower alkylenedioxy group present at any possibleposition on the benzene ring as a substituent, the number ofsubstituents being 1 to 4; the other symbols have the same definitionsas those shown above; in place of compound (VI) in scheme 1 above.

Of the compounds included in the compound (I) or the compound (II), acompound wherein R² is a lower alkyl group that may have a substituent,namely a compound (XIV) or compound (XIV′), can, for example, beproduced by the method shown by scheme 2 below.

With respect to the compounds (XII) to (XIV) or compounds (XII′) to(XIV′) in scheme 2 above, R¹¹ represents a lower alkyl group that mayhave a substituent; the other symbols have the same definitions as thoseshown above.

Also, the compound (I) or compound (II) can also be synthesized by acompound represented by formula (XV) or (XV′) by the method shown inscheme 3 below.

With respect to the compounds (XV) to (XV′) in scheme 3 above, R¹²represents a hydrogen atom or a lower alkyl group that may besubstituted; the other symbols have the same definitions as those shownabove.

Examples of the lower alkyl group represented by R⁹ to R¹² are a linearor branched C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Examples of the substituent of the lower alkyl group the substituent ofthe homo- or hetero-cycle represented by the mentioned above ring A′.

Provided that, R¹¹ does not include a hydroxymethyl group.

The respective reactions of schemes 1 to 3 in the above-describedproduction methods are hereinafter described in more detail.

Reaction processes 1 and 2 can be carried out in accordance withcommonly known methods (e.g., J. G. Smith et al., Journal of OrganicChemistry, Vol. 53, pp. 2,942-2,953 (1988); T. Kuroda et al., Journal ofChemical Society Chemical Communications, pp. 1,635-1,636 (1991); T.Kuroda et al., Journal of Organic Chemistry, Vol. 59, pp. 7,353-7,357(1994)).

Specifically, in reaction process 1, the compound [VI] or compound [VI′]is produced by treating the compound [VI] or compound [IV′] with a baseto produce a dianion, and condensing it with the compound [V].

The base used is exemplified by alkyllithiums; preferable alkyllithiumsinclude, for example, n-butyllithium, sec-butyllithium,tert-butyllithium, methyllithium and phenyllithium, with greaterpreference given to n-butyllithium. The amount of alkyllithium used isnormally 2 to 10 mol, preferably 2 to 3 mol, per mol of the compound[IV] or compound [IV′].

The amount of the compound [V] used is normally 0.5 to 10 mol,preferably 1 to 3 mol, per mol of the compound [IV] or compound [IV′].

Also, said reaction can be advantageously carried out in a solvent. Thesolvent used is a solvent that does not adversely affect the reaction.Useful solvents include, for example, hydrocarbons (e.g., pentane,hexane, cyclohexane, benzene), ethers (e.g., diethyl ether,tetrahydrofuran, dioxane), amides (e.g., hexamethylphosphoric triamide)and ureas (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine).These solvents may be used singly, or in mixtures of 2 or more kindsmixed in appropriate ratios or as mixed solvents with water. The amountof solvents used is normally 1 to 100 milliliters, preferably 5 to 20milliliters, per gram of the compound [IV] or compound [IV′].

Reaction temperature for the base and the compound [IV] or compound[IV′] is normally −72° C. to 200° C., preferably 0° C. to 50° C.Reaction time is normally 30 minutes to 24 hours, preferably 30 minutesto 12 hours.

Reaction temperature for the subsequent condensation with the compound[V] is normally −72° C. to 200° C., preferably 0° C. to 50° C. Reactiontime is normally 30 minutes to 72 hours, preferably 30 minutes to 18hours.

In reaction process 2, the compound [VIII] or compound [VIII′] isproduced by treating the compound [VI] or compound [VI′] with an acidproduce a condensed furan derivative in the reaction system, andcondensing it with the compound [VII].

The acid used is an inorganic acid or an organic acid; preferableinorganic acids include, for example, hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid and polyphosphoricacid. Preferable organic acids include, for example, formic acid, aceticacid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonicacid. The amount of acid used is normally 0.01 to 10 mol, preferably0.03 to 2 mol, per mol of the compound [VI] or compound [VI′].

The amount of the compound [VII] used is normally 1 to 10 mol,preferably 1 to 3 mol, per mol of the compound [IV] or compound [VI′].

Also, said reaction can be advantageously carried out in a solvent. Thesolvent used is a solvent that does not adversely affect the reaction;useful solvents include, for example, hydrocarbons (e.g., pentane,hexane, cyclohexane, benzene, toluene), lower alcohols (e.g., methanol,ethanol, propanol), ethers (e.g., diethyl ether, tetrahydrofuran,dioxane) and halogenated hydrocarbons (e.g., dichloromethane,chloroform, 1,2-dichloroethane). Also, when the above-mentioned acidsare liquid, they may be used as solvents. These solvents may be usedsingly, or in mixtures of 2 or more kinds mixed in appropriate ratios ofas mixed solvents with water. The amount of solvents used is normally 1to 100 milliliters, preferably 5 to 20 milliliters, per gram of thecompound [VI] or compound [VI′].

Reaction temperature is normally −20° C., preferably 25° C. to 150° C.

Reaction time is normally 30 minutes to 24 hours, preferably 30 minutesto 12 hours.

In reaction process 3, the compound (IX) or compound (IX′) is producedby subjecting the compound (VIII) or compound (VIII′) to a hydrolyticreaction.

Said hydrolytic reaction can, for example, be carried out using acommonly known method (S. R. Sandler and W. Karo, “Organic FunctionalGroup Preparations I,” 2nd ed., Academic Press (1983), Chapter 9 (pp.271-273)).

Also, when said hydrolytic reaction is carried out under acidicconditions, reaction process 4 can take place simultaneously withreaction process 3 to yield the compound (X) or compound (X′).

In reaction process 4, the compound (X) or compound (X′) is produced bysubjecting the compound (IX) or compound (IX′) to an aromatizingreaction for simultaneous dehydration and decarboxylation.

Although said aromatizing reaction is normally carried out by treatingthe compound (IX) or compound (IX′) with an acid, it can also be carriedout by keeping standing or heating the compound (IX) or compound (IX′)under neutral conditions.

The acid used is an inorganic acid or an organic acid; preferableinorganic acids include, for example, hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid and polyphosphoricacid. Preferable organic acids include, for example, formic acid, aceticacid, trifluoroacetic acid, trichloroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonicacid. The amount of acid used is normally 0.01 to 10 mol, preferably0.03 to 2 mol, per mol of the compound (IX) or compound (IX′).

Also, said reaction can be advantageously carried out in a solvent. Thesolvent used is a solvent that does not adversely; affect the reaction;useful solvents include, for example, hydrocarbons (e.g., pentane,hexane, cyclohexane, benzene), lower alcohols (e.g., methanol, ethanol,propanol), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane) andhalogenated hydrocarbons (e.g., dichloromethane, chloroform,1,2-dichloroethane). Also, when the above-mentioned acids are liquid,they may be used as solvents. These solvents may be used singly, or inmixtures of 2 or more kinds mixed in appropriate ratios or as mixedsolvents with water. The amount of solvent used is normally 1 to 100milliliters, preferably 5 to 20 milliliters, per gram of the compound(IX) or compound (IX′). Reaction temperature is normally about −20° C.to about 200° C., preferably about 25° C. to about 150° C. Reaction timeis normally 30 minutes to 24 hours, preferably 30 minutes to 12 hours.

In reaction process 5, the compound (XI) or compound (XI′) is producedby subjecting the compound (X) or compound (X′) to an amidatingreaction, followed by an acylating reaction as necessary.

Said amidating reaction can, for example, be carried out using acommonly known method (S. R. Sandler and W. Karo, “Organic FunctionalGroup Preparations I,” 2nd ed., Academic Press (1983), Chapter 11 (pp.315-358)).

Said acylating reaction can, for example, be carried out using acommonly known method (S. R. Sandler and W. Karo, “Organic FunctionalGroup Preparations I,” 2nd ed., Academic Press (1983), Chapter 7 (pp.281-313)).

In reaction process 6, the compound [XIII] or compound [XIII′] isproduced by subjecting the compound [XII] or compound [XII′] to aring-opening reaction, followed by an acylating reaction as necessary.

The compound [XII] or compound [XII′], serving as the starting material,may, for example, be a lactone compound produced by commonly knownmethods (R. S. Burden et al. Journal of the Chemical Society Section C,pp. 693-701, 1969; Archives of Pharmacology, 328(9), pp. 640-644, 1995;Indian Journal of Chemistry, Section B: Org. Chem. Include. Med. Chem.,33B(9), pp. 839-846, 1994; Indian Journal of Chemistry, Section B:31B(7), pp. 401-406, 1992; Chemical and Pharmaceutical Bulletin, 32(1),pp. 31-37, 1984; Journal of the Chemical Society Section C, (11), pp.2,091-2,094, 1971; Phytochemistry 29(9), pp. 2,991-2,993, 1990; Journalof Natural Products, 43(4), pp. 482-486, 1980; M. Anazini et al.,Heterocycles, Vol. 38, pp. 103-111, 1994, etc.) or modification thereof.

The ring-opening reaction is carried out by reacting the compound [XII]or compound [XII′] with ammonia or an amine derivative represented byHR¹ (R¹ has the same definition as that shown above).

The ammonia used is aqueous ammonia or gaseous or liquid ammonia.

The amount of ammonia or amine derivative used is normally 1 mol toabout 100 mol, preferably 2 to 10 mol, per mol of the compound [XII] orcompound [XII′].

The reaction can be advantageously carried out in a solvent. The solventused is a solvent that does not adversely affect the reaction; usefulsolvents include for example, hydrocarbons (e.g., pentane, hexane,cyclohexane, benzene), lower alcohols (e.g., methanol, ethanol,propanol), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane),amides (e.g., N,N-dimethylformamide, hexamethylphosphoric triamide) andureas (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine). Also,when the amine derivative represented by HR¹ (R¹ has the same definitionas that shown above) is liquid, it can also be used as a solvent. Thesesolvents may be used singly, or in mixtures of 2 or more kinds mixed inappropriate ratios or as mixed solvents with water. The amount ofsolvent used is normally 1 to 100 milliliters, preferably 5 to 20milliliters, per gram of the compound [XII] or compound [XII′]. Reactiontemperature is normally −20° C. to 200° C., preferably 25° C. to 150°C.; in some cases, the reaction can be advantageously carried out in asealed tube.

Also, when the R¹ in HR¹ (R¹ has the same definition as that shownabove) is an acylated amino group, said reaction can be advantageouslyproceeded in the presence of a base.

The base used is exemplified by alkyllithium reagents (e.g.,methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium,preferably n-butyllithium); inorganic bases (e.g., sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogen carbonate, potassium hydrogen carbonate, cesium carbonate,sodium hydride, metallic sodium) and organic bases (e.g., sodiummethoxide, sodium ethoxide, triethylamine, pyridine,diethylisopropylamine). The amount of base used is normally 1 to about10 mol, preferably 1 to 2 mol, per mol of the compound [XII] or compound[XII′].

Reaction time is normally 30 minutes to 1 week, preferably 30 minutes to4 days.

The acylating reaction carried out after the ring-opening reaction asnecessary can, for example, be carried out using the method describedfor reaction process 5.

In reaction process 7, the compound (XIV) or compound (XIV′) is producedby subjecting the compound (XIII) or compound (XIII′) to a functionalgroup-converting reaction, a carbon-adding reaction or an appropriatecombination thereof.

Said functional group-converting reaction or carbon-adding reaction can,for example, be carried out by commonly known methods (J. Mathieu and J.Weil-Raynal, “Formation of C—C Bonds I-III, ” George Thieme Publishers,Stuttgart (1973, 1975, 1979); S. R. Sandler and W. Karo, “OrganicFunctional Group Preparations I-III,” 2nd ed., Academic Press (1983,1986, 1989) etc.).

In reaction process 8, the compound (I) or compound (II) is produced bysubjecting the compound (XV) or compound (XV′) to an amidating reaction,followed by an acylating reaction as necessary.

The compound (XV) or compound (XV′), serving as the starting material,may, for example, be a carboxylic acid derivative produced by commonlyknown methods (e.g., G. Jones ed., “Quinolines Part 1, ” John Wiley &Sons (1977), Chapter 2 (pp. 93-318); L. S. El-Assal et al., Journal ofChemical Society, pp. 1,658-1,662, (1961); D. Delorme et al., Journal ofMedicinal Chemistry, Vol. 39, pp. 3,951-3,970, (1996)) or modificationsthereof.

The amidating reaction can, for example, be carried out using a commonlyknown method (S. R. Sandler and W. Karo, “Organic Functional GroupPreparations I,” 2nd ed., Academic Press (1983)), Chapter 11 (pp.315-358)).

The acylating reaction can, for example, be carried out using the methoddescribed for reaction process 5.

Also, when the desired compound is produced by the methods shown byschemes 1 through 3 above, and provided that the substituents or rings Aand B in the compounds (IV) through (XV) and the compounds (IV′) through(XV′) contain a functional group such as a hydroxyl group, an aminogroup, a mono-C₁₋₆ alkylamino group, a ketone, a carboxyl group or atetrazolyl group, for example, these functional groups may be protected;regarding the kind of protecting group, and methods of protection anddeprotection, a commonly known method (T. W. Green and P. G. M. Wuts,“Protective Groups in Organic Chemistry,” 2nd ed., John Wiley & Sons,Inc., (1991)) etc. are used.

The thus-obtained compound (I), compound (II) or a salt thereof can beisolated and purified by commonly known means (e.g., redissolution,concentration, solvent extraction, fractional distillation,crystallization, recrystallization, chromatography).

Also, the salt of the compound (I) or compound (II) of the presentinvention is preferably a pharmaceutically acceptable salt, exemplifiedby salts with inorganic bases, salts with organic bases, salts withinorganic acids, salts with organic acids, and salts with basic oracidic amino acids. Preferable salts with inorganic bases include, forexample, alkali metal salts (e.g., sodium salt, potassium salt),alkaline earth metal salts (e.g., calcium salt, magnesium salt),aluminum salt and ammonium salt. Preferable salts with organic basesinclude, for example, salts with trimethylamine, triethylamine,pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N′-dibenzylethylenediamine etc.

Preferable salts with inorganic acids include, for example, salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid etc.

Preferable salts with organic acids include, for example, salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidetc.

Preferable salts with basic amino acids include, for example, salts witharginine, lysine, ornithine etc.

Preferable salts with acidic amino acids include, for example, saltswith aspartic acid, glutamic acid etc. Also, when the desired product isobtained in free form, it may be converted to a salt by a conventionalmethod; when the desired product is obtained as a salt, it may beconverted to the free compound by a conventional method.

The compound (I) or compound (II) of the present invention or a saltthereof may be a hydrate or non-hydrate.

The compound (I) or compound (II) or a salt thereof may be isolated andpurified by commonly known means, e.g., solvent extraction, liquidnature conversion, redissolution, crystallization, recrystallization andchromatography. Also, although the starting compound for the compound(I) or compound (II) or a salt thereof may be isolated and purified bythe same known means as those shown above, it may be used as a startingmaterial for the next process as a reaction mixture as is withoutisolation.

When the compound (I) or compound (II) of the present invention or asalt thereof contains an optical isomer, a stereoisomer, a positionisomer or a rotational isomer, these isomers are also included in thescope of the compounds of the present invention, and each can beobtained as a single product by commonly known means of synthesis orseparation. For example, when an optical isomer is present in thecompound of the present invention, the optical isomer resolved from saidcompound is also included in the scope of the present invention.

An optical isomer can be produced by commonly known methods.Specifically, an optical isomer is obtained by using an optically activesynthesis intermediate or by optically resolving the final racematemixture by a conventional method.

Useful methods of optical resolution include commonly known methods,e.g., the fractional recrystallization method, chiral column method anddiastereomer method described below.

(1) Fractional recrystallization method

A salt of a racemate and an optically active compound is formed andseparated by the fractional recrystallization method to yield a freeoptical isomer via a neutralization process is desired.

(2) Chiral column method

A racemate or a salt thereof is applied to a column for optical isomerseparation (chiral column) to separate it. In the case of liquidchromatography, for example, optical isomers are separated by adding amixture thereof to a chiral column such as ENANTIO-OVm (produced byTosoh Corporation), and developing it in water, various buffers (e.g.,phosphate buffer) and organic solvents (e.g., ethanol, methanol,acetonitrile) as a simple or mixed solution. Also, in the case of gaschromatography, for example, a chiral column such as CP-Chirasil-DeX CB(produced by GL Science) is used to separate optical isomers.

(3) Diastereomer method

A diastereomer mixture, prepared from a racemate mixture using anoptically active reagent and chemical reaction, is treated by ordinarymeans of separation (e.g., fractional recrystallization, chromatography)etc. to obtain a single substance, after which the optically activereagent moiety is cut off by a chemical treatment such as hydrolysisreaction. When the compound of the present invention has a hydroxylgroup or a primary or secondary amino group in the molecular structurethereof, an ester or amide diastereomer, respectively, is obtained bysubjecting said compound, an optically active organic acid (e.g., MPTA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-methoxyaceticacid) etc. to a condensation reaction. On the other hand, when thecompound (I) of the present invention has a carboxylic acid group, anester or amide diastereomer, respectively, is obtained by subjectingsaid compound and an optically active amine or an alcohol reagent to acondensation reaction. The diastereomer separated is converted to anoptical isomer of the original compound by an acid hydrolysis or basichydrolysis reaction.

The cell differentiation induction factors serving as targets of thepresent invention include factors which induce a charactercharacteristic of the process of differentiation of undifferentiatedprecursors of cells which maintain living body function in particulartissue, such as osteoblasts and neurons, e.g., factors belonging to theTGF-β superfamily such as bone morphogenetic protein, neurotrophicfactors, transforming growth factor (TGF)-β and activin, factorsbelonging to the FGF superfamily such as basic fibroblast growth factor(bFGF) and acidic fibroblast growth factor (aFGF), factors belonging tothe neuropoietic cytokine family such as leukemia inhibitory factor(LIF, or also called cholinergic differentiation factor (CDF)) andciliary neurotrophic factor (CNTF), interleukin 1 (IL-1, hereinaftersimilarly abbreviated), IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-11, tumornecrosis factor-α (TNF-α) and interferon-γ (INF-γ), with preferencegiven to bone morphogenetic protein and neurotrophic factors.

Bone morphogenetic factors include members of the MBP family of proteinswhich promote osteogenesis and chondrogenesis, such as BMP-2, -4, -5,-6, -8, -9, -10, -11 and -12, with preference given to BMP-2, -4, -6 and-7. BMP may be a homo-dimer of each of the above-mentioned factors or ahetero-dimer consisting of any possible combination thereof.

Neurotrophic factors include nerve growth factor (NGF), brain-derivedneurotrophic factor (BDNF) and neurotrophic-3 (NT-3) and glial cellline-derived neurotrophic factor (GDNF), with preference given to theNGF family.

The compound (I) or compound (II) of the present invention or a saltthereof can be safely administered orally or non-orally (e.g., topical,rectal and intravenous administration), as such or in the form ofpharmaceutical compositions formulated with a pharmaceuticallyacceptable carrier, e.g., tablets (including sugar-coated tablets andfilm-coated tablets), powders, granules, capsules (including softcapsules), syrups, emulsions, suspensions, injectable preparations(e.g., subcutaneous, intradermal, intramuscular injections),suppositories and sustained-release preparations, in accordance with acommonly known method. The content of compound (I), compound (II) or asalt thereof in the preparation of the present invention 0.1 to 100% byweight relative to the entire preparation. Varying depending on subjectof administration, route of administration, target disease etc., thedaily dose of the compound (I) or (II) of the present invention or asalt thereof is normally about 0.1 to 500 mg, preferably about 1 to 100mg, and more preferably about 5 to 100 mg, per day, based on the activeingredient, per adult (60 kg), administered in 1 to several portions perday, when it is used in a cell differentiation induction factor actionagent or an enhancer for said action, for example.

Said injectable preparation is used by a commonly known method, i.e.,the compound (I) or (II) or a salt thereof is used as such or incombination with a substance exhibiting cell differentiation inductionfactor action, e.g., BMP or neurotrophic factor. Aqueous solutions forinjection include physiological saline and isotonic solutions, and maybe used as necessary in combination with the suspending agents shownbelow. Oily liquids include sesame oil and soybean oil, and may be usedin combination with the dissolution aids shown below. The injectablepreparation prepared is normally filled in appropriate ampules.

Pharmacologically acceptable carriers used to produce the preparation ofthe present invention are various organic or inorganic carriersubstances in common use as pharmaceutical materials, includingexcipients, lubricants, binders and disintegrants for solidpreparations, and solvents, dissolution aids, suspending agents,isotonizing agents, buffers and soothing agents for liquid preparations.Other pharmaceutical additives such as preservatives, antioxidants,coloring agents, sweetening agents, adsorbents and wetting agents may beused as necessary. Excipients include, for example, lactose, sucrose,D-mannitol, starch, corn starch, crystalline cellulose and light silicicanhydride. Lubricants include, for example, magnesium stearate, calciumstearate, talc and colloidal silica.

Binders include, for example, crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose and carboxymethl cellulose sodium.

Disintegrants include, for example, starch, carboxymethyl cellulose,carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethylstarch sodium and L-hydroxypropyl cellulose.

Solvents include, for example, water for injection, alcohol, propyleneglycol, macrogol, sesame oil and corn oil.

Dissolution aids include, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Suspending agents include, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride andmonostearic glycerol; and hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose andhydroxypropyl cellulose.

Isotonizing agents include, for example, glucose, D-sorbitol, sodiumchloride, glycerol and D-mannitol.

Buffers include, for example, buffer solutions of phosphates, acetates,carbonates, citrates etc.

Soothing agents include, for example, benzyl alcohol.

Preservatives include, for example, p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Antioxidants include, for example, sulfites and ascorbic acid.

Since a pharmaceutical composition containing the compound (I) orcompound (II) or a salt thereof exhibits excellent celldifferentiation-inducing action and cell differentiation-inducing factoraction-enhancing action, it is useful in the treatment and prevention ofvarious nerve diseases (e.g., diseases based on nerve degeneration, suchas those in cerebrovascular dementia, senile dementia or Alzheimer'sdisease; motor neuronal disease such as amyotrophic lateral scelerosis(Lou Gehrig disease); or diabetic peripheral neuropathy) or bone/jointdiseases (e.g., bone fractures, osteoporosis, osteoarthritis, rheumatoidarthritis); specifically, agents for treating or preventing bone/jointdiseases include, for example, osteogenesis promoters, cartilagedestruction suppressors, bone fracture healing promoters or bonereconstruction promoters, when used alone or in combination withsubstances exhibiting cell differentiation induction factor action(e.g., BMP, neurotrophic factors).

Furthermore, because not all roles of BMP, neurotrophic factor, etc. inthe living body have been clarified, it is likely that pathologiccondition can be improved in other diseases by enhancing the actions ofBMP, neurotrophic factors, etc. The cell differentiation-inducing actionagent or cell differentiation-inducing factor action-enhancing agent ofthe present invention can also be used as an agent for treating orpreventing such diseases associated with BMP, neurotrophic factors, etc.

The cell differentiation-inducing action agent or celldifferentiation-inducing factor action-enhancing agent of the presentinvention can be used in the above-mentioned diseases not only in humansbut also in other mammals (e.g., mice, rats, rabbits, dogs, cats,bovines, pigs).

Also, a pharmaceutical composition containing the compound (I) orcompound (II) of the present invention or a salt thereof is of lowtoxicity and has few side effects.

The cell differentiation-inducing action agent or celldifferentiation-inducing factor action-enhancing of the presentinvention can be mixed in a carrier for bone reconstruction as anosteogenesis promoter in bone repair and bone transplantation because itpossesses potent osteogenesis-promoting activity. For example, thecompound of the present invention can be used as adhered to, orcontained in, artificial bones etc. prepared from metals, ceramics orhigh-molecular substances. The artificial bone is preferably made porouson the surface thereof to allow the cell differentiation inductionfactor action enhancer of the present invention to be released in livingtissue upon its transplantation to a bone defect. The compound of thepresent invention can be adhered to, or contained in, an artificial boneby dispersing it in an appropriate dispersant, binder, diluent or thelike (e.g., collagen, physiological saline, citric acid solution, aceticacid solution, hydroxyapatite, fibrin, mixture thereof) and applying itto, or impregnating it in, the artificial bone, followed by drying. Suchartificial bone is transplanted to a bone defect and firmly fixed to thedefect. An artificial bone fixative can be prepared by mixing the activeingredient helioxanthine with dispersants, binders, diluents, othercomponents effective on bone regeneration (e.g., calcium), etc. that arephysiologically acceptable for pharmaceutical use. The artificial bonefixative can also be used to fill in the gap between the artificial bonetransplanted to the bone defect in the hose and the bone defect, withoutadhering it to, or containing it in, the artificial bone. It should benoted that the non-oral composition described here can also be used withan osteogenesis-promoting protein such as the BMP family adhered theretoor contained therein.

Mode of Working The Invention

The present invention is described in more detail by the followingReference Examples, Examples, Formulation Examples and ExperimentalExamples but they are merely illustrative and should not be construed aslimiting the scope of the invention. Thus, many modifications may bemade without from the scope of the invention.

In the column chromatography in the following Reference Examples andExamples, elutions (developing solvent was indicated in brackets) werecarried out under thin-layer chromatography monitoring.

The TLC monitoring was carried out using Kieselgel 60F₂₅₄ (layerthickness 0.25 mm, Merck) for TLC plates, the solvents which were usedin the column chromatography as developers, UV detector andphosphomolyvdate color reaction for detector. As silica gel for columnchromatography, Kieselgel 60 (70-230 mesh, Merck) was used. The NMRspectra represent proton NMR (¹H-NMR) spectra, which were measured withGemini 200 (produced by Varian) using tetramethylsilane either asinternal or external standard and expressed in δ (ppm).

The infrared absporption Spectra were recorded with IR-810spectrophotometer (Nippon Bunko Kogyo). The melting points weredetermined with the Yanagimoto micromelting point meter MP-500D and theuncorrected values were shown. The “room temperature” in the followingReference and Working Examples means 0° C.-30° C., preferably about 15°C.-25° C.

In the chemical formulas in the following Examples and ReferenceExamples, Me stands for methyl and Ms for methanesulfonyl. The othersymbols or abbreviations used in the present specification have thefollowing meanings.

S singlet d doublet dd double doublet t triplet m multiplet br broad Jcoupling constant Hz Hertz THF tetrahydrofuran DMF N,N-dimethylformamideDME dimethoxyethane CDCl deuterochloroform DMSO-d₆deuteromethylsulfoxide NMR proton nuclear magnetic resonance

REFERENCE EXAMPLE 110-(4-Methoxyphenyl)-furo[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one

Butyl lithium (1.6M hexane solution: 36 ml) was added dropwise to asolution of helioalcohol (4.0 g) in benzene (200 ml) at roomtemperature. The mixture was stirred at room temperature for two hours,followed by addition of a solution of 4-methoxybenzonitrile (3.9 g:1.1equivalent) in benzene (50 ml). The mixture was stirred at roomtemperature overnight, followed by addition of water and extraction withether. The organic layer was washed with water, dried over magnesiumsulfate and concentrated under reduced pressure. The residue wasdissolved in toluene (250 ml), followed by addition of maleic anhydride(7.7 g) and p-toluenesulfonic acid (1.0 g). The mixture was refluxed for20 hours, and the precipitated solid was filtered off. The filtrate wasconcentrated under reduced pressure. Conc. HCl was added to the residue.The mixture was refluxed for one hour and cooled to room temperature.The resulting yellowish brown precipitate was collected by suction,washed with water and recrystallized from THF to yield acid anhydride(about 3.4 g). Sodium borohydride (0.8 g) was suspended in DME (80 ml),followed by addition of the above anhydride at 0° C. The mixture wasstirred at 0° C. for 30 minutes and poured into ice-cooled diluted HC.The resulting product was extracted with ethyl acetate. The extract wasdried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (eluent:chloroform) toyield the title compound (1.5 g). Some portions of the compound wasrecrystallized from THF to be used for elemental and instrumentalanalysis.

m.p.: 217-219° C.

NMR (CDCl₃) δ: 3.90 (3H,s), 5.20 (2H,s), 5.93 (2H,s), 6.99 (1H,d,J=9Hz), 7.28 (1H,d,J=9 Hz), 7.32 (1H,d,J=9 Hz), 7.72 (1H,d,J=9 Hz), 8.43(1H,s).

Elemental Analysis for C₂₀H₁₄O₅·0.5H₂O

Calcd: C, 70.58%; H, 4.34%

Found: C, 70.52%; H, 4.38%

REFERENCE EXAMPLE 210-(4-Chlorophenyl)-furo[3′,4′;6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one

The title compound was produced in a similar manner to that in ReferenceExample 1.

m.p.: 225-227° C.

NMR (CDCl₃) δ: 5.18 (2H, s), 5.93 (2H,s), 7.33 (3H,m), 7.44 (2H,d,J=8Hz), 7.73 (1H,d,J=8 Hz), 8.45 (1H,s).

Elemental Analysis for C₁₉H₁₁O₄Cl·0.2H₂O

Calcd: C, 66.66%; H, 3.36%

Found: C, 66.59%; H, 3.14%

Reference Example 310-(2-Naphthyl)-furo[3′,4′;6,7]naphtho[1,2-d]dioxol-7(9H)-one

The title compound was produced in a similar manner to that in ReferenceExample 1.

m.p.: 224-226° C.

NMR (CDCl₃) δ: 5.13(1H,d,J=15.2 Hz), 5.29 (1H,d,J=15.2 Hz), 5.85(1H,d,J=1.4 Hz), 5.85 (1H,d,J=1.4 Hz), 7.334 (1H,d,J=8.8 Hz), 7.43(1H,d,J=8.2 Hz, 1.8 Hz), 7.57 (2H,m), 7.75 (1H,d,J=8.8 Hz), 7.8-8.0(4H,m), 8.48 (1H,s).

Elemental Analysis for C₂₃H₁₄O₄

Calcd: C, 77.96%; H, 3.98%

Found: C, 77.57%; H, 4.10%

REFERENCE EXAMPLE 4 10- (4-Fluorophenyl)-furo[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one

The title compound was produced in a similar manner to that in ReferenceExample 1.

m.p.: 215-218° C.

NMR (CDCl₃) δ: 5.18 (2H,s), 5.92(2H,s), 7.15 (2H,m), 7.33 (3H,m) 7.73(1H,d,J=8.8 Hz), 8.45 (1H,s).

Elemental Analysis for C₁₉H₁₁O₄F

Calcd: C, 70.81%; H, 3.44%

Found: C, 70.57%; H, 3.65%

REFERENCE EXAMPLE 510-(4-Methylphenyl)-furo[3′,4′,:6,7]naphtho[1,2-d]-1,3 -dioxol-7(9H)-one

The title compound was produced in a similar manner to that in ReferenceExample 1.

m.p.: 208 -210° C.

NMR (CDCl₃) δ: 1.45 (3H,s), 5.19(2H,s), 7.25(4H,s), 7.32(1H,d,J=8.4 Hz),7.72(1H, d,J=8.4 Hz), 8.43 (1H,s).

Elemental Analysis for C₂₀H₁₄O₄

Calcd: C, 75.46%; H, 4.43%

Found: C, 75.17%; H, 4.52%

REFERENCE EXAMPLE 610-(1,3-Benzodioxole-5-yl)-1,3-dioxolo[4,5-f]furo[3,4-b]quinolin-7(9H)-one

Diethyl 9-(1,3-benzodioxole-5-yl)-1,3-dioxolo[4,5-f]furo[3,4-b]quinoline-7(9H)-one dicarboxylate (2.4 g) was addedgradually to a suspension of LAH (lithium aluminium hydride (2.0 g) inTHF (50 ml) at 0° C. The mixture was stirred at room temperature for onehour, followed by addition of water to stop the reaction. The resultingprecipitate was filtered off through Celite®. The filtrate was extractedwith ethyl acetate. The extract was washed with water, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in ethanol (100 ml) and, with addition of 10% Pd-C (2.5g), stirred at room temperature overnight. The catalyst was filteredoff, and the solvent was distilled off under reduced pressure. Theresidue was dissolved in chloroform (300 ml), followed by addition ofmanganese dioxide (20 g). The mixture was stirred at room temperaturefor 3 hours. The manganese dioxide was filtered off through Celite®. Thefiltrate was concentrated under reduced pressure. The resulting crudecrystals were washed with diisopropyl ether to yield the title compound(0.9 g). Some portions of the compound were recrystalized from THF to beused for elemental and instrumental analysis.

m.p.: 272-274° C.

NMR (CDCl₃) δ: 5.30(1H,d,J=16 Hz), 5.41(1H,d,J=16 Hz), 6.05(2H,d,J=4Hz), 6.10(2H,d,J=4 Hz), 6.86(2H,m), 6.95(1H,d,J=8 Hz), 7.57(1H,d,J=9Hz), 8.11(1H,d,J=9 Hz).

Elemental Analysis for C₁₉H₁₁NO₆

Calcd: C, 65.33%; H, 3.17%; N, 4.01%

Found: C, 64.91%; H, 3.07%; N, 4.18%

REFERENCE EXAMPLE 7 5-Phenyl-7-methyl-furo[3,4-b]quinolin-2 (4H)-one

The title compound was produced in a similar manner to that in ReferenceExample 6.

m.p.: 191-193° C.

NMR (CDCl₃) δ: 2.52(3H,s), 5.38(2H,s), 7.40-7.50(2H,m), 7.57-7.75(5H,m),8.34(1H,d,J=9 Hz).

IR(KBr): 1780, 1500, 1455, 1372, 1131, 1054 cm⁻¹

Elemental Analysis for C₁₈H₁₃NO₂

Calcd: C, 78.53%; H, 4.76%; N, 5.09%

Found: C, 78.37%; H, 4.71%; N, 5.18%

REFERENCE EXAMPLE 85-(2,4-Difluorophenyl)-7-methyl-furo[3,4-b]quinolin-2 (4 H)-one

The title compound was produced in a similar manner to that in ReferenceExample 6.

m.p.: 218-220° C.

NMR (CDCl₃) δ: 2.54(3H,s), 5.29(1H,d,J=15 Hz), 5.39(1H,d,J=15 Hz),7.06-7.21(2H,m), 7.34-7.50(2H,m), 7.72(1H,dd,J=1.8 Hz,8 Hz), 8.36(1Hz,d,J=8 Hz).

IR(KBr): 1768, 1500, 1455, 1423, 1374, 1142, 1093, 1060 cm⁻¹

Elemental Analysis for C₁₈H₁₁F₂ NO₂

Calcd: C, 69.45%; H, 3.56%; N, 4.50%

Found: C, 69.33%; H, 3.56%; N, 4.59%

REFERENCE EXAMPLE 99-(4-Methoxyphenyl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid

Butyl lithium (1.6M hexane solution: 36 ml) was added dropwise to asolution of helioalcohol (4.0 g) in benzene (100 ml) at roomtemperature. The mixture was stirred at room temperature for one hour,followed by addition of 4-methoxybenzonitrile (3.85 g) in benzene (20ml). The mixture was stirred at room temperature overnight, followed byaddition of water and extraction with ether. The organic layer waswashed with water, dried over magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in toluene (75 ml), followedby addition of dimethyl fumarate (7.58 g) and trichloroacetic acid (0.3g). The mixture was refluxed for 3 hours and concentrated under reducedpressure. The reside was dissolved in ethyl acetate and washed withwater, an aqueous saturated sodium hydrogen carbonate solution andbrine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified with silica gel column chromatography(silica gel: 50 g. eluent:ethyl acetate−hexane=1:2) to yieldtetrahydro-2,4-epoxynaphthalene derivative (2.84 g) as a mixture ofdiastereoisomers. This was dissolved in a mixture of THF (5 ml) andmethanol (5 ml), followed by addition of an aqueous NaOH (1.1 g)solution (5 ml). The mixture was stirred overnight and concentratedunder reduced pressure. After being diluted with water, the mixture waswashed with ethyl acetate. Conc. HCl was added to the aqueous layeruntil its pH becomes about 2.The mixture was extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfateand concentrated under reduced pressure. The residue was dissolved inether (50 ml), followed by addition of conc. HCl. The mixture wasrefluxed for 10 minutes and concentrated under reduced pressure,followed by addition of water. The resulting precipitate was collectedby filtration and washed with methanol and ether to yield the titlecompound (2.64 g).

m.p.: 264-266° C.

NMR (CDCl₃+CD₃OD) δ: 3.89(3H,s), 5.95(2H,s), 6.90-7.00(2H,m),7.27(1H,d,J=9 Hz), 7.34-7.43(2H,m), 7.64(1H,d,J=9 Hz), 7.86(1H,d,J=1.6Hz), 8.55(1H,d,J=1.6 Hz).

REFERENCE EXAMPLE 109-(4-Trifluoromethylphenyl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid

The title compound was produced in a similar manner to that in ReferenceExample 9.

m.p.: 207-209° C.

NMR (DMSO) δ: 6.02(2H,s), 7.52(1H,d,J=8 Hz), 7.69(1H,d,J=8 Hz),7.72(1H,d,J=1.4 Hz),l 7.78(1H,d,J=8 Hz), 7.92(1H,d,J=8 Hz),8.66(1H,d,J=1.4 Hz).

REFERENCE EXAMPLE 119-(1,3-Benzodioxole-5-yl)-6-methyl-naphtho[1,3-d]1,3-dioxole-7-carboxylicacid

The title compound was produced in a similar manner to that in ReferenceExample 9.

m.p.: 233-235° C.

NMR (CDCl₃+DMSO) δ: 2.96(3H,s), 5.94(2H,s), 6.02(2H,s), 6.79-6.93(3H,m),7.27(1H,d,J=9 Hz), 7.69(1H,s), 7.86(1H,d,J=9 Hz).

REFERENCE EXAMPLE 12 9-(1,3-Benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid

The title compound was produced in a similar manner to that in ReferenceExample 9.

m.p.: 267-269° C.

NMR (DMSO) δ: 6.03(2H,s), 6.09(2H,s), 6.89(1H,dd,J=1.5 Hz, 8 Hz),6.96(1H,d,J=8 Hz), 7.00(1H,d,J=1.5 Hz), 7.47(1H,d,J=9 Hz),7.66(1H,d,J=1.6 Hz), 7.86(1H,d,J=9 Hz), 8.57(1H,d,J=1.6 Hz).

REFERENCE EXAMPLE 139-(1,3-Benzodioxole-5-yl)-8-methyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylicacid (a) Methyl9-(1,3-benzodioxole-5-yl)-8-methanesulfonyloxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylate

1N NaOH solution (2.9 ml) was added to a solution of helioxanthin (1 g)in DMF (10 mol). The mixture was heated at 60° C. for 30 minutes. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin DMF (10 ml), followed by addition of methyl iodine. The mixture washeated at 60° C. for one hour. The solvent was distilled off underreduced pressure. Water was added to the residue. The mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in THF (10 ml), followed by addition oftriethylamine (0.80 ml). Methanesulfonylchloride (0.22 ml) was addeddropwise to the mixture under ice-cooling. The mixture was stirred for30 minutes, followed by addition of water. The mixture was extractedwith ethyl acetate. The extract was washed with brine, dried overmagnesium sulfate and concentrated under reduced pressure to yield thetitle compound (1.25 g). The crude compound thus produced was used inthe subsequent reaction without further purification.

NMR (CDCl₃) δ: 3.00(3H,s), 3.91(3H,s), 5.24(1H,d,J=10 Hz),5.34(1H,d,J=10 Hz), 5.91(1H,d,J=1.2 Hz), 5.94(1H,d,J=1.2 Hz),6.09(1H,d,J=0.8 Hz), 6.13(1H,d,J=0.8 Hz), 6.73(1H,dd,J=1.6 Hz, 8 Hz),6.86(1H,d,J=1.6 Hz), 6.98(1H,d,J=8 Hz), 7.49(1H,d,J=9 Hz), 7.81(1H,d,J=9Hz), 8.54(1H,s).

(b) Methyl9-(1,3-benzodioxole-5-yl)-8-methyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylate

Sodium borohydride (36 mg) was added to a solution of methyl9-(1,3-dioxole-5-yl)-8-methanesulfonyloxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylate(443 mg) in DMF (5 ml), and the mixture was stirred overnight.

Water was added to the mixture to stop the reaction. The product wasextracted with ether. The extract was washed with brine, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified with column chromatography (silica gel: 50 g, eluent: ethylacetate: hexane=1:4) to yield the title compound (1.5 g).

NMR (CDCl₃) δ: 2.34(3H,s), 3.95(3H,s), 5.81(1H,d,J=1.5 Hz),5.82(1H,d,J=1.5 Hz), 6.03(1H,d,J=1.4 Hz), 6.06(1H,d,J=1.4 Hz),6.67(1H,dd,J=1.6 Hz, 8 Hz) 6.70(1H,d,J=1.6 Hz), 6.86(1H,d,J=8 Hz),7.16(1H,d,J=9 Hz), 7.49(1H,d,J=9 Hz), 8.33(1H,s).

(c) 9-(1,3-Benzodioxole-5-yl)-8-methyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid

Methyl9-(1,3-benzodioxole-5-yl)-8-methyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylatewas dissolved in a mixture of THF (6 ml) and methanol (3 ml). Afteraddition of 1N NaOH (3 ml), the mixture was stirred for 4 days. 1N HClwas added to the reaction mixture, followed by addition of water. Theresulting precipitate was collected by filtration to yield the titlecompound (264 mg). Some portions of the compound was recrystalized frommethanol-chloroform to be used for elemental and instrumental analysis.

NMR (DMSO) δ: 2.24(3H,s), 5.83(1H,brs), 5.86(1H,brs), 6.05(1H,brs),6.11(1H,brs), 6.65(1H,dd,J=1.6 Hz,8 Hz), 6.78(1H,d,J=1.6 Hz),6.94(1H,d,J=8 Hz), 7.32(1H,d,J=8 Hz), 7.68(1H,d,J=8 Hz), 8.37(1H,s).

REFERENCE EXAMPLE 14 9-(1,3-Benzodioxole-5yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid. (a) Methyl9-(1,3-benzodioxole-5-yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylate

5-Amino-1,3-benzodioxole-4-yl 1,3-benzodioxole-4-yl ketone (2.7 g) and2-ketobutyric acid methyl ester (1.9 g) were dissolved in acetic acid(30 ml), followed by addition of sulfuric acid (0.3 ml). The mixture wasrefluxed for 1.5 hours and then concentrated under reduced pressure.Water was added to the residue, followed by extraction with ethylacetate. The extract was washed with aqueous sodium hydrogen carbonatesolution and water successively, dried over magnesium sulfate andconcentrated under reduced pressure to yield the title compound asyellow crystals (2.6 g).

m.p.: 174-177° C.

NMR (CDCl₃) δ: 2.30(3H,s), 4.04(3H,s), 5.89(2H,m), 6.06(2H,m),6.68(2H,m), 6.89(1H,d,J=8 Hz), 7.36(1H,d,J=9 Hz), 7.81(1H,d,J=9 Hz).

Elemental Analysis for C₁₉H₁₃NO₆

Calcd: C, 64.96%; H, 3.73%: N, 3.99%

Found: C, 65.02%; H, 3.90%; N, 3.92%

(b)9-(1,3-Benzodioxole-5-yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid

2.5% aqueous NaoH solution (20 ml) was added to a solution of9-(1,3-benzodioxole-5-yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid methyl ester in methanol (20 ml). The mixture was refluxed for onehour. 1N HCl was added to the reaction mixture to make it slightlyacidic (pH 5), followed by extraction with ethyl acetate. The extractwas washed with water, dried over magnesium sulfate and concentratedunder reduced pressure to yield the title compound as yellow crystals(252 mg). Some portions of the compound were recrystalized from THF tobe used for elemental and instrumental analysis.

m.p.: 219-222° C.

NMR (CDCl₃) δ: 2.59(3H,s), 5.93(2H,m), 6.07O2H,d,J=5 Hz), 6.67(2H,m),6.90(1H,d,J=8 Hz), 7.43(1H,d,J=9 Hz), 7.76(1H,d,J=9 Hz).

Elemental Analysis for C₁₉H₁₃NO₆

Calcd: C, 64.96%; H, 3.73%; N, 3.99%

Found: C, 65.02%; H, 3.90%; N, 3.92%

REFERENCE EXAMPLE 1510-(4-Trifluoromethoxyphenyl)-furo[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one

In the same manner as in Reference Example 1, the title compound wasobtained.

Melting point: 222-225° C.

NMR (CDCl₃( δ: 5.19(2H,s), 5.92(2H,s), 7.25-7.45(5H,m), 7.73(1H,d,J=8.8Hz), 8.46 (1H,s).

Elemental analysis for C₂₀H₁₁F₃O₅

Calcd: C, 61.86%; H, 2.86%

Found: C, 64.79%; H, 2.79%

REFERENCE EXAMPLE 169-(4-Trifluoromethoxyphenyl)-naphtho[1,2-d]-1,3-dioxol-7-carboxylic acid

In the same manner as in Reference Example 9, the title compound wasobtained.

Melting point: 296-300° C.

NMR (CDCl₃) δ: 5.94(2H,s), 6.82(2H,s), 7.20-7.90(4H,m), 8.58(1H,m).

IR (KBr): 2880, 1676, 1279 cm⁻¹

REFERENCE EXAMPLE 174-(1,3-Benzodioxol-5-yl)-6.7-diethoxy-naphtho[2,3-c]furan-1(3 H)-one

In the same manner as in Reference Example 6, the title compound wasobtained.

NMR (CDCl₃) δ: 1.47(3H,t,J=7 Hz), 1.57(3H,t,J=7 Hz), 4.04(2H,q,J=7 Hz),4.26(2H,q,J=7 Hz), 5.22(2H,s), 6.08(1H,d,J=1.4 Hz), 6.12(1H,d,J=1.4 Hz),6.80-6.90(2H,m), 6.99(1H,d,J=9 Hz), 7.09(1H,s), 7.30(1H,s), 8.28(1H,s).

REFERENCE EXAMPLE 1810)-4-Trifluoromethoxyphenyl)-1,3-dioxolo[4,5-f]furo[3,4-b]quinolin-7(9H)-one

In the same manner as in Reference Example 6, the title compound wasobtained.

NMR (CDCl₃) δ: 5.33(2H,s), 6.02(2H,s), 7.30-7.50(3H,m), 7.58(1H,d,J=9Hz), 8.13(1H,d,J=9 Hz).

REFERENCE EXAMPLE 195-(1,3-Benzodioxol-5-yl)-7)-methoxyfuro[3,4-b]quinolin-2(4 H)-one

In the same manner as in Reference Example 6, the title compound wasobtained.

NMR (CDCl₃) δ: 3.85(3H,s), 5.36(2H,s), 6.13(2H,s), 6.85-7.10(3H,m),7.17(1H,d,J=3 Hz), 7.51(1H,dd,J=3,10 Hz), 8.32(1H,d,J=10 Hz).

Reference Example 208-(1,3-Benzodioxol-5-yl)-naphtho[2,3-d]-1,3-dioxole-6-carboxylic acid

To a solution of 5-bromo-6-hydroxymethyl-1,3-benzodioxol (5.0 g) inether (100 ml), butyl lithium (1.6M solution in hexane, 30 ml) was addeddropwise at −78° C. After stirring at 0° C. for 1 hour, the solution wasagain cooled to −78° C.; a solution of 5-cyano-1,3-benzodioxol (3.52 g)in ether (50 ml) was added dropwise. After stirring at room temperaturefor 3 hours, water was added, followed by extraction with ethyl acetate.After being washed with brine, the organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in toluene (100 ml); dimethyl fumarate (3.13 g) andtrichloroacetic acid (0.83 g) were added. The mixture was refluxed for 1hour and concentrated under reduced pressure. The residue obtained wasdissolved in ethyl acetate and washed with a saturated aqueous solutionof sodium hydrogen carbonate and brine. After being dried with magnesiumsulfate, the mixture was concentrated under reduced pressure; theresidue was purified by column chromatography (silica gel: 50 g, eluent:ethyl acetate−hexane=1:2) to yield a tetrahydro-1,4-epoxynaphthalenederivative (3.30 g) as a diastereomer mixture. This was dissolved in THF(15 ml) and methanol (15 ml); an aqueous solution (5 ml) of sodiumhydroxide (1.24 g) was added, followed by overnight stirring. Thereaction mixture was concentrated under reduced pressure and dilutedwith water, after which it was washed with ethyl acetate Afterconcentrated hydrochloric acid was added to the water layer until the pHreached about 2, the product was extracted with ethyl acetate. Theextract was washed with brine, after which it was dried over magnesiumsulfate and concentrated under reduced pressure. The residue obtainedwas dissolved in ether (10 ml); concentrated hydrochloric acid (0.5 ml)was added; followed by stirring at room temperature for 3 hours. Afterthe reaction mixture was concentrated under reduced pressure, water wasadded; the resulting precipitate was washed with methanol and ether toyield the title compound (0.38 g).

NMR (DMSO) δ: 6.10(2H,s), 6.12(2H,s), 6.80-7.10(4H,s), 7.42(1H,s),7.81(1H,s), 8.35(1H,s).

REFERENCE EXAMPLE 21 6-Chloro-4-(4-chlorophenyl)naphtho[2,3-c]furan-1 (3H)-one

To a suspension of sodium borohydride (0.5 g) in dimethoxyethane (20ml), a solution of 6-chloro-4-(4-chlorophenyl)naphtho[2,3-c]furan-1,3-dione (1.0 g) in THF (20 ml) was added dropwise,followed by stirring at room temperature for 1 hour. The reactionmixture was poured into 1N hydrochloric acid to stop the reaction; theproduct was extracted with ethyl acetate. After being washed with water,the extract was dried over magnesium sulfate and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (eluent: hexane−ethyl acetate=3:1) and recrystallizedfrom THF to yield the title compound (300 mg).

m.p. 205-207° C.

NMR (CDCl₃) δ: 5.25(2H,s), 7.33(2H,d,J=8.4 Hz), 7.58(3H,m), 7.72(1H,s),8.05(1H,d,J=9.2 Hz), 8.51(1H,s).

IR (KBr): 1771, 1632, 1491 cm⁻¹

Elemental analysis for C₁₈H₁₀Cl₂O₂) Calcd: C, 65.68%; H, 3.06%. Found:C, 65.11%; H, 2.92%.

REFERENCE EXAMPLE 225-(4-Fluorophenyl)-3,4-dihydro-7-methoxy-1H-pyrano[3,4-b]quinolin-1-one(a) Ethyl3-ethoxycarbonylmethyl-4-(4-fluorophenyl)-6-methoxyquinoline-2-carboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (CDCl₃) δ: 1.21(3H,t, J=7.0 Hz), 1.46(3H,t,J=7.0 Hz), 3.71(3H,s),3.85(2H,s), 4.11(2H,q,J=7.0 Hz), 4.51(2H,q,J=7.0 Hz), 6.54(1H,d,J=2.4Hz), 7.25(4H,m), 7.39(1H,dd,J=7.6,2.4 Hz), 8.18(1H,d,J=9.6 Hz).

(b)2-[4-(4-Fluorophenyl)-2-hydroxymethyl-6-methoxyquinolin-3-yl]-1-ethanol

To a suspension of lithium aluminum hydride (180 mg) in THF (15 ml),ethyl3-ethoxycarbonylmethyl-4-(4-fluorophenyl)-6-methoxyquinoline-2-carboxylate(1.0 g) was added, followed by stirring at 0° C. for 30 minutes. Waterwas added to the reaction mixture to stop the reaction; after theinsoluble substances were filtered off, the product was extracted withethyl acetate. After being washed with water, the extract was dried overmagnesium sulfate and concentrated under reduced pressure to yield acrude crystal (1 g) of the title compound. The crude crystal obtainedwas used for the next reaction without further purification.

NMR (CDCl₃) δ: 2.79(2H,t,J=7.4 Hz), 3.62(2H,t,J=7.4 Hz), 3.69(3H,s),4.97(2H,s), 6.51(1H,d,J=3.0 Hz), 7.27(4H,m), 7.33(1H,dd,J=9.0,3.0 Hz),8.00(1H,d,J=9.0 Hz).

(c)5-(4-Fluorophenyl)-3,4-dihydro-7-methoxy-1H-pyrano[3,4-b]quinolin-1-one

To a solution of a crude crystal (1.0 g) of2-[4-(4-fluorophenyl)-2-hydroxymethyl-6-methoxyquinolin-3-yl]-1-ethanolin chloroform (100 ml), manganese dioxide (10 g) was added, followed bystirring at room temperature for 2 hours. After the manganese dioxidewas filtered off, the reaction mixture was concentrated under reducedpressure; the residue obtained was recrystallized from THF to yield thetitle compound (335 mg).

m.p.: 240-241° C.

NMR (CDCl₃) δ: 2.99(2H,t,J=5.8 Hz), 3.76(3H,s), 4.54(2H,t,J=5.8 Hz),6.71(1H,d,J=3.0 Hz), 7.30(4H,m), 7.43(1H,dd,J=9.6,3.0 Hz),8.31(1H,d,J=9.6 Hz).

IR (KBr): 2959, 2926, 1740, 1620, 1497 cm⁻¹

Elemental analysis for C₁₉H₁₄FNO₃ Calcd: C, 70.58%; H, 4.36%; N, 4.33%.Found: C, 70.49%; H, 4.57%; N, 4.26%.

REFERENCE EXAMPLE 2311-(1,3-Benzodioxol-5-yl)-9,10-dihydro-7H-1,3-dioxolo[4,5-f]pyrano[3,4-b]quinolin-7-one(a) Ethyl9-(1,3-benzodioxol-5-yl)-8-ethoxycarbonylmethyl-1,3-dioxolo[4,5-f]quinolin-7-carboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (CDCl₃) δ: 1.21(3H,t,J=7.1 Hz), 1.44(3H,t,J=7.2 Hz), 3.86(2H,s),4.12(2H,q,J=7.1 Hz), 4.49(2H,q,J=7.2 Hz), 5.89(2H,m), 6.06(2H,m),6.68(1H,d,J=7.6 Hz), 6.72(1H,s), 6.86(1H,d,J=7.6 Hz), 7.41(4H,d,J=8.8Hz), 7.89(1H,d,J=8.8 Hz).

(b)2-[9-(1,3-Benzodioxol-5-yl)-7-hydroxymethyl-1,3-dioxolo[4,5-f]quinolin-8-yl]-1-ethanol

In the same manner as in Reference Example 22 (b), the title compoundwas obtained.

NMR (CDCl₃) δ: 1.76(1H,bs), 2.78(2H,t,J=7.4 Hz), 3.63(2H,t,J=7.4 Hz),4.92(2H,s), 5.24(1H,brs), 5.83(1H,d,J=1.4 Hz), 5.85(1H,d,J=1.4 Hz),6.04(1H,d,J=1.4 Hz), 6.07(1H,d,J=1.4 Hz), 6.67(1H,dd,J=7.8,0.8 Hz),6.70(1H,d,J=0.8 Hz), 6.87(1H,d,J=7.8 Hz), 7.32(1H,d,J=8.8 Hz),7.67(1H,d,J=8.8 Hz).

(c)11-(1,3-Benzodioxol-5-yl)-9,10-dihydro-7H-1,3-dioxolo[4,5-f]pyrano[3,4-b]quinolin-7-one

In the same manner as in Reference Example 22 (c), the title compoundwas obtained.

NMR (CDCl₃) δ: 3.00(2H,dt,J=1.8,5.9 Hz), 4.51(2H,t,J=5.9 Hz),5.95(1H,d,J=1.4 Hz), 5.97(1H,d,J=1.4 Hz), 6.06(1H,d,J=1.4 Hz),6.09(1H,d,J=1.4 Hz), 6.65-6.80(2H,m), 6.91(1H,d,J=7.6 Hz),7.47(1H,d,J=8.8 Hz), 8.05(1H,d,J=8.8 Hz).

REFERENCE EXAMPLE 24 6-Chloro-4-(4-pyridyl)-2-quinolinecarboxylic acid(a) Ethyl 6-chloro-4-(4-pyridyl)-2-quinolinecarboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (CDCl₃) δ: 1.50(3H,t,J=7.0 Hz), 4.58(2H,q,J=7.0 Hz),7.46(2H,dd,J=4.4,1.8 Hz), 7.73-7.85(2H,m), 8.15(1H,s), 8.35(1H,d,J=8.8Hz), 8.85(2H,dd,J=4.4,1.4 Hz).

Elemental analysis for C₁₇H₁₃N₂O₂Cl Calcd: C, 65.29%; H, 4.19%; N,8.96%. Found: C, 65.01%; H, 4.12%; N, 8.98%.

(b) 6-Chloro-4-(4-pyridyl)-2-quinolinecarboxylic acid

In the same manner as in Reference Example 14 (b), the title compoundwas obtained.

NMR (CDCl₃) δ: 3.36(1H,brs,COOH), 7.66(2H,d,J=5.8 Hz), 7.82(1H,d,J=2.2Hz), 7.95(1H,dd,J=8.8,2.2 Hz), 8.06(1H,s), 8.29(1H,d,J=8.8 Hz),8.82(2H,d,J=5.8 Hz).

Elemental analysis for C₁₅H₉N₂O₂Cl.0.1H₂O Calcd: C, 62.88%; H, 3.24%; N,9.78%. Found: C, 62.72%; H, 3.34%; N, 9.75%.

REFERENCE EXAMPLE 259-(4-Methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid (a)Ethyl 9-(4-methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (CDCl₃) δ: 1.43(3H,t,J=2.7 Hz), 3.90(3H,s), 4.54(2H,q,J=7.2 Hz),6.02(2H,s), 6.99(2H,d,J=8.8 Hz), 7.43(2H,d,J=8.8 Hz), 7.48(1H,d,J=8.8Hz), 7.96(1H,s), 8.03(1H,d,J=8.8 Hz).

(b) 9-(4-Methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid

In the same manner as in Reference Example 14 (b), the title compoundwas obtained.

NMR (CDCl₃) δ: 3.83(3H,s), 6.09(2H,s), 7.02(2H,d,J=8.6 Hz),7.48(2H,d,J=8.6 Hz), 7.70(1H,d,J=8.8 Hz), 7.77(1H,s), 7.87(1H,d,J=8.8Hz).

REFERENCE EXAMPLE 269-(1,3-Benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid(a) Ethyl9-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (CDCl₃) δ: 1.48(3H,t,J=7.2 Hz), 4.54(2H,q,J=7.2 Hz), 6.04(2H,s),6.06(2H,s), 6.87-7.00(3H,m), 7.48(1H,d,J=9.0 Hz), 7.96(1H,s),8.03(1H,d,J=9.0 Hz).

(b) 9-(1,3-Benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid

In the same manner as in Reference Example 14 (b), the title compoundwas obtained.

NMR (CDCl₃+DMSO-d₆) δ: 6.06(4H,s), 6.87-7.00(3H,m), 7.50(1H,d,J=9.2 Hz),7.97(1H,d,J=9.2 Hz), 8.00(1H,s).

REFERENCE EXAMPLE 279-(4-Fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid (a)Ethyl 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (DMSO-d₆) δ: 1.38(3H,t,J=7.4 Hz), 4.43(2H,q,J=7.4 Hz), 6.11(2H,s),7.26-7.37(2H,m), 7.57-7.62(2H,m), 7.74(1H,d,J=8.8 Hz), 7.81(1H,s),7.93(1H,d,J=8.8 Hz).

(b) 9-(4-Fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid

In the same manner as in Reference Example 14 (b), the title compoundwas obtained.

NMR (CDCl₃+DMSO-d₆) δ: 6.03(2H,s), 7.05-7.20(2H,m), 7.35-7.55(3H,m),7.95-8.05(2H,m).

REFERENCE EXAMPLE 28 Methyl3-bromomethyl-6-methoxy-4-(4-methoxyphenyl)quinoline-2-carboxylate (a)Methyl 6-methoxy-4-(4-methoxyphenyl)-3-methylquinoline-2-carboxylate

In the same manner as in Reference Example 14 (a), the title compoundwas obtained.

NMR (CDCl₃) δ: 2.35(3H,s), 3.71(3H,s), 3.92(3H,s), 4.05(3H,s),6.66(1H,d,J=3 Hz), 7.00-7.25 (4H,m), 7.33(1H,dd,J=3.9 Hz), 8.09(1H,d,J=9Hz).

(b) Methyl3-bromomethyl-6-methoxy-4-(4-methoxyphenyl)quinoline-2-carboxylate

Methyl 6-methoxy-4-(4-methoxyphenyl)-3-methylquinoline-2-carboxylate(8.27 g) was dissolved in benzene (100 ml); N-bromosuccinimide (5.24 g)and 2,2′-azobis(isobutyronitrile) (0.40 g) were added; followed byrefluxing for 2 hours. After cooling to room temperature, the resultingprecipitate was filtered off. The filtrate was diluted with ethylacetate (100 ml), after which it was washed with 1 N sodium hydroxideand brine successively, and dried over magnesium sulfate. The solventwas distilled off under reduced pressure; the residue obtained waspurified by column chromatography (silica gel: 50 g, eluent: ethylacetate-hexane=1:2). The crude crystal obtained was recrystallized fromethyl acetate-hexane to yield the title compound (9.93 g) as a colorlessneedle crystal.

NMR (CDCl₃) δ: 3.72(3H,s), 3.94(3H,s), 4.10(3H,s), 4.84(2H,s),6.66(1H,d,J=3 Hz), 7.05-7.35(4H,m), 7.40(1H,dd,J=3.9 Hz), 8.14(1H,d,J=9Hz).

REFERENCE EXAMPLE 29 Ethyl8-chloro-1,3-dioxolo[4,5-g]quinoline-6-carboxylate

After a mixture of 3,4-(methylenedioxy)aniline (10 g),acetylenedicarboxylic acid diethyl ester (15 g) and ethyl alcohol (150ml) was refluxed for 20 hours, the solvent was distilled off underreduced pressure. To the residue, diphenyl ether (50 ml) was added,followed by heating at 200° C. for 1.5 hours. After cooling, thereaction mixture was diluted with isopropyl ether to yield3-hydroxy-1,3-dioxolo[4,5-g]quinoline-6-carboxylic acid ethyl ester as abrown crystal (10.6 g). After a mixture of the crystal obtained (10.4g), phosphoryl chloride (22.4 ml) and benzene (170 ml) was stirred atroom temperature for 3 days, the reaction mixture was poured into waterand stirred at room temperature for 30 minutes. After this mixture wasextracted with ethyl acetate, the extract was washed with brine anddried over magnesium sulfate; the solvent was distilled off underreduced pressure to yield the title compound as a brown crystal (8.59g).

NMR (CDCl₃) δ: 1.48(3H,t,J=7.1 Hz), 4.53(2H,q,J=7.1 Hz), 6.20(2H,s),7.52(1H,s), 7.58(1H,s), 8.13(1H,s).

REFERENCE EXAMPLE 30 Ethyl8-(1-piperidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate

A mixture of ethyl 8-chloro-1,3-dioxolo[4,5-g]quinoline-6-carboxylate(300 mg) as obtained in Reference Example 29, piperidine (0.5 ml) andethyl alcohol (5 ml) was heated at 140° C. in a sealed tube for 17hours. After the solvent was distilled off under reduced pressure, theresidue was purified by column chromatography using silica gel(hexane-ethyl acetate=3:1) to yield the title compound as a colorlesscrystal (73.6 mg).

NMR (CDCl₃) δ: 1.47(3H,t,J=7.1 Hz), 1.71(2H,m), 1.84(4H,m), 3.15(4H,m),4.52(2H,q,J=7.1 Hz), 6.12(2H,s), 7.29(1H,s), 7.51(1H,s), 7.60(1H,s).

REFERENCE EXAMPLE 31 Ethyl8-(1-pyrrolidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate

In the same manner as in Reference Example 30, the title compound wasobtained.

NMR (CDCl₃) δ: 1.46(3H,t,J=7.1 Hz), 2.05(4H,m), 3.66(4H,m),4.50(2H,q,J=7.1 Hz), 6.08(2H,s), 7.29(1H,s), 7.46(1H,s), 7.51(1H,s).

REFERENCE EXAMPLE 32 Ethyl8-(4-morpholinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate

In the same manner as in Reference Example 30, the title compound wasobtained.

NMR (CDCl₃) δ: 1.48(3H,t,J=7.2 Hz), 3.20(4H,m), 3.98(4H,m),4.53(2H,q,J=7.2 Hz), 6.14(2H,s), 7.31(1H,s), 7.54(1H,s), 7.63(1H,s).

REFERENCE EXAMPLE 33 Ethyl8-(4-methylpiperazin-1-yl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate

In the same manner as in Reference Example 30, the title compound wasobtained.

NMR (CDCl₃) δ: 1.47(3H,t,J=7.0 Hz), 2.42(3H,s), 2.71(4H,m), 3.24(4H,m),4.53(2H,q,J=7.2 Hz), 6.13(2H,s), 7.30(1H,s), 7.53(1H,s), 7.62(1H,s).

EXAMPLE 1N-Methyl-9-(1,3-benzodioxole-5-yl)-8-hydroxymethylnaphtho[1,2-d]-1,3-dioxole-7-carboxamide

Helioxanthin (1.0 g) was suspended in benzene (10 ml), followed byaddition of methylamine (40% methanol solution: 2 ml). The mixture washeated at 120° C. under stirring for 4 days. The reaction mixture wasconcentrated under reduced pressure. The resulting residue wasrecrystalized from DMF to yield the title compound (144 mg).

m.p.: 233-235° C.

NMR (DMSO-d₆) δ: 2.83(3H,d,J=5 Hz), 4.27(2H,d,J=6 Hz), 4.95(1H,t,J=6Hz), 5.85(1H,s), 5.85(1H,s), 6.06(1H,s), 6.12(1H,s), 6.70(1H,dd,J=1.6Hz,8 Hz), 6.81(1H,d,J=1.6 Hz), 6.93(1H,d,J=8 Hz), 7.37(1H,d,J=9 Hz),7.63(1H,d,J=9 Hz), 8.01(1H,s), 8.55-8.70(1H,m).

IR(KBr): 3340, 1615, 1485, 1445, 1435, 1280, 1065 cm⁻¹

Elemental Analysis for C₂₁H₁₇NO₆.0.2H₂O Calcd: C, 63.47%; H, 4.82%; N,3.52%. Found: C, 63.50%; H, 4.61%; N, 3.81%.

EXAMPLE 2N-Methyl-9-(4-methoxyphenyl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example1, using10-(4-methoxyphenyl)furo[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxole-7(9H)-one

m.p.: 187-190° C.

NMR (CDCl₃) δ: 3.07(3H,d,J=5 Hz), 3.88(3H,s), 4.37(2H,s), 5.79(2H,s),6.56(1H,brs), 6.93(2H,d,J=8 Hz), 7.19(1H,d,J=9 Hz), 7.23(2H,d,J=8 Hz),7.44(1H,d,J=9 Hz), 7.93(1H,s).

Elemental Analysis for C₂₁H₁₉NO₅ Calcd: C, 69.03%; H, 5.24%; N, 3.83%.Found: C, 68.92%; H, 5.27%; N, 3.77%.

EXAMPLE 3N-Methyl-9-(4-chlorophenyl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example1, using10-(4-chlorophenyl)furo[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxole-7(9H)-onewhich was obtained in Reference Example 2.

m.p.: 202-204° C.

NMR (CDCl₃) δ: 3.08(3H,d,J=5 Hz), 4.35(3H,m), 5.80(2H,s), 6.42(1H,brs),7.26(3H,m), 7.38(2H,d,J=8 Hz), 7.46(12H,d,J=8 Hz), 7.96(1H,s).

Elemental Analysis for C₂₀H₁₆ClNO₄ Calcd: C, 64.96%; H, 4.36%; N, 3.79%.Found: C, 64.94%; H, 4.62%; N, 3.85%.

EXAMPLE 4N-Methyl-9-(2-naphthyl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example1, using10-(2-naphthyl)furo[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxole-7(9H)-one whichwas obtained in Reference Example 3.

m.p.: 207-210° C.

NMR (CDCl₃) δ: 3.07(3H,d,J=5 Hz), 4.36(3H,m), 5.64(2H,m), 6.56(1H,brs),7.22(1H,m), 7.49(4H,m), 7.84(4H,m), 7.99(1H,s).

Elemental Analysis for C₂₄H₁₉NO₄ Calcd: C, 74.79%; H, 4.97%; N, 3.63%.Found: C, 74.28%; H, 5.21%; N, 3.60%.

EXAMPLE 5N-Methyl-9-(4-fluorophenyl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamidePCS-TEXT

The title compound was produced in a similar manner to that in Example1, using 10-(4-fluorophenyl)-furo[3′,4′:6,7]naphtho[1,2,-d]-1,3-dioxol-7(9H)-one which was obtainedin Reference Example 4.

m.p: 210-213° C.

NMR (CDCl₃) δ: 3:08(3H,d,J=5 Hz), 4.36(3H, m) 5.79(2H,s), 6.48(1H,brs),7.09(2H,t,J=9 Hz), 7.27(3H,m), 7.46(1H,d,J=8 Hz), 7.95(1H,s).

Elemental Analysi for C₂₀H₁₆FNO₄ Calcd: C, 67.98%; H, 4.56%; N, 3.96%Found: C, 67.90%; H, 4.75%; N, 3.94%

EXAMPLE 6N-Methyl-9-(4-methylphenyl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example1, using 10-(4-methoxphenyl)-furo [3′,4′:6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)- one which was obtained in Reference Example 5.

m.p.: 210-212° c.

NMR (CDCl₃) δ: 2.43(3H, s), 3.07(3H,d,J=5 Hz), 4.20-4.40 (3H, m), 5.78(2H,s), 6.51 (1H,brs), 7.20 (5H,m), 7.45 (2H,d,J=H,z), 7.05 (1H,s).

Elemental Analysis for C₂₁H₁₉NO4 Calcd: C, 72.19%; H, 5.48%; N, 4.01%Found: C, 71.85%; H, 5.79%; N, 3.94%

EXAMPLE 7 N-Methyl-(1,3-benzodioxole-5-yl)-7-hydroxymethyl-naphto[2,3-d]-1,3-dioxole-6-carboxamide

The title compound was produced in a similar manner to that in Example1, using 9-(1,3-benzodioxole-5-yl)-furo[3′,4′:6,7]naphtho[2,3-d]-1,3-dioxol-6(8H)-one (Justicidin E: K.Ohta., et al., Tetrahedron lett., 1970, 923).

m.p.: 222-224° C.

NMR (CDCl₃) 67 : 3:07(3H,d,J=5 Hz), 4.30-4.50(3H,m), 6.05(4H,m),6.51(1H,brs), 6.77(3H,m), 9.94(1H,d,J=7 Hz), 7.11(1H,s), 7.83(1H,s).

Elemental Analysis for C₂₁H₁₇NO₆ Calcd: C, 66.49%, H, 4:52%; N, 3.69%Found: C, 66.35%, H, 4.73%; N, 3.61%

EXAMPLE 89(1,3-Benzodioxole-5-yl)-8hydroxymethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

The title compound was produced in a similar manner to that in Example1, using a10-(1,3-benzodioxole-5-yl)-8,9-dihydro-9H-1,3-dioxolo[4,5-f]pyrolo[3,4-b]quinolin-7-onewhich was obtained in Reference Example 6.

NMR (CDCl₃) 67 : 4.50-4.75(2H,m) 5.02(1H,d,J=8 Hz), 5.72(1H,m),5.91(1H,d,J=1.4 Hz), 5.93(1H,d,J=1.4 Hz), 6.08(1H,d,=1.2 Hz),6.75-6.83(2H,m), 6.89(1H,d,J=8 Hz), 7.43(1H,d,J=9 Hz), 7.75(1H,d,J=9Hz), 8.15(1H,m).

Elemental Analysis for C₁₉H₁₄N₂O₆ Calcd: C, 62.30%; H, 3.85%; N, 7.65%Found: C, 62.13%; H, 3.89%; N, 7.37%

EXAMPLE 9N-methyl-(3-hydroxmethyl-6-methyl-4-phenylquinoline)-2-carboxamide

The title compound was produced in a similar manner to that in Example1, using 5-phenyl-7-methyl-furo[3,4-b]quinolin-2(4H)-one which wasobtained in Reference Example 7.

m.p.: 136-137° C.

NMR (CDCl₃) δ: 2.43(3H,s) 3.13(3H,d,J=5 Hz), 4.64(2H,d,J=8 Hz),5.37(1H,d,J=8 Hz), 7.23(1H,brs,) 7.30-7.40(2H,m), 7.48-7.52(4H,m),7.98(1H,d,J=8 Hz), 8.44(1H,m).

IR(KDr): 3460, 3398, 1652, 1533, 1488, 1421, 1025 cm ⁻¹

Elemental Analysis for C₁₉H₁₈N₂O₂ Calcd: C, 74.49%; H, 5.92%; N, 9.14%Found: C, 74.28%; H, 5.95%; N, 9.20%

EXAMPLE 10 N-Methyl-[3-hydroxymethyl-6-methyl-4-(2,4-difluorophenyl)quinoline]-2-carboxamide

The title compoud was produced in a similar manner to that in Example 1,using 5-(2,4-diflurophenyl)-7-methyl-furo [3,4-b]quinolin-2(4H)-onewhich was obtained in Reference Example 8.

m.p.: 140-141° C.

NMR (CDCl₃) δ: 2.46(3H,s), 3.13(3H,dJ=5 Hz), 4.46(2H, dd,J=10Hz,13 Hz),4.84(1H,dd,J=6Hz, 13 Hz), 5.38(1H,dd,J=6 Hz), 6.98-7.16(3H,m),7.30-7.42(1H,m), 7.59(1H,dd,J=1.8Hz, 8 Hz), 8.02(1H,d,J=8 Hz),8.42(1H,m).

IR(KBr): 3464, 3402, 1652, 1509, 1139, 1023, 969 cm⁻¹

Elemental Analysis for C₁₉H₁₆F₂N₂O₂ Calcd: C, 66.66%; H, 4.71%; N, 8.18%Found: C, 66.55%; H, 4.71%; N, 8.23%

EXAMPLE 11 9(4-Methoxyphenyl)-naphtho[1,2,-d]-1,3,-dioxole-7-carboxamide

9-(4Methoxphenyl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid (200 mg),which was produced in Reference Example 9, was suspended in THF (6 ml),followed by addition of DMF (1 drop). Oxalyl chlordie (0.1 ml) wasdropwise added to the resulting mixture at room temperature. The mixturewas stirred at room temperature for one hour. The resulting reactionmixture was concentrated under reduced pressure to yield crude9-(4-methoxphenyl)-naphtho[1,2-d]-1,3-dioxole-7carboxy chloride. Asolution of the above produced acid chloride in THF (3 ml) was dropwiseadded to a mixture of a conc. aquous ammonia solution (2 ml) and THF (1ml) under ice-cooling. After being stirred for 30 minutes, the reactionmixture was extracted by ethyl acetate. The extract was washed withbring, dried over magnesium sulfate and concentrated under reducedpressure. The resulting residue was recrystalized from ethanol to yieldthe tile compound (134 mg).

m.p.: 187-189° C.

NMR (CDCl₃) δ: 3.89(3H,s), 6.90-7.00(2H,m), 7.28(1H,d,J=8 Hz),7.33-7.41(2H,m), 7.61(1H,d,J=1.6 Hz), 7.62(1H,d,J=8 Hz), 8.31(1H,d,J=6Hz).

IR(KBr): 3365, 3168, 1681, 1666, 1459, 1288, 1245, 1052 cm⁻¹

Elemental Analysis for C₁₉H₁₅NO₄ Calcd: C, 71.02%; H, 4.71%; N,4.36%Found: C, 70.77%; H, 4.71%; N, 4.47%

EXAMPLE 129-(4-Trifluromethylphenyl)-naphto[1,2-d]-1,3-dixole-7-carboxamide

The title compound was produced in a similar manner to that in Example11, using9-(4-trifluromethylphenyl)-naphtho[1,2,-d]-1,3-dioxole-7-carboxylic acidwhich was produced in Reference Example 10.

m.p.: 207-209° C.

NMR (CDCl₃) δ: 5.90(2H,brs), 5.94(2H,s), 7.31(1H,d,J=8 Hz),7.57(2H,brs,J=8 Hz), 7.64(1H,d,J=8 Hz), 7.65(1H,d,J=8 Hz), 7.67(2H,d,J=8Hz), 8.34(1H,d,J=8 Hz).

IR(KBr): 3487, 3147, 1685, 1463, 1328, 1293, 1108, 1072 cm⁻¹

Elemental Analysis for C₁₉H₁₂F₃NO₃ Calcd: C, 63.51%; H, 3.37%; N, 3.90%Found: C, 63.21%; H, 3.63%; N, 4.02%

EXAMPLE 139-(1,3-Benzodioxole-5-yl)-6-methyl-naphto[1,2-d]-1,3-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example11, using 9-(1,3-benzodioxole-5-yl)-6-methyl-naphto[1,2-d]-1,3,-dioxole-7carboxylic acid.

m.p.: 237-239° C.

NMR(DMSO-d₆) δ: 2.67(3H,brs), 5.98(2H,brs), 6.07(2H,brs),6.82-7.00(3H,m), 7.15(1H,brs), 7.44(1H,d,J=9 Hz), 7.52(1H,brs),7.80(1H,brs.), 7.85(1H,brs).

IR(KBr): 3398, 3178,1648, 1615, 1492, 1378, 1251, 1054 cm⁻¹

Elemental Analysis for C₂₀H₁₅NO₅ Calcd: C, 68.76%; H, 4.33%; N, 4.01%Found: c, 68.40%; H, 4.31%; N, 4.05%

EXAMPLE 149-(1,3-Benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example11, using 9-(1,3-benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid which was prepared in ReferenceExample 12.

m.p.: 267-269° C.

NMR (DMSO-d₆) δ: 6:01(2H,s), 7.08(2H,s), 6.90(1H,dd,J=1.4Hz,8 Hz),6.97(1H,d,J=8 Hz), 7.01(1H,d,J=1.4 Hz), 7.43(1H,brs), 7.44(1H,d,J=9 Hz),7.72(1H,d,J=1.6 Hz), 7.73(1H,d,J=9 Hz), 8.12(1H,brs), 8.46(1H,d,J=1.6Hz).

IR(KBr): 3460, 1677, 1486, 1465, 1280, 1233, 1052 cm⁻¹

Elemental Analysis for C₁₉H₁₃NO₅ Calcd: C, 68.06%; H, 3.91%; N, 4.18%Found: C, 67.81%; H, 3.91%; N, 4.17%

EXAMPLE 15 N-Methyl-9-(1,3-benzodioxole-5-yl)-naphtho;[1,2,-d]-1,3-dioxole-7-carboxamide

The title compund was produced in a similar manner to that in Example11, using 9(1,3-benzodioxole-5yl) -naphtho[1,2,-d]-1,3-sioxole-7-carboxylic acid which was prepared in ReferenceExample 12 and conducting a condensation reaction with methylamine (40%methanol solution.

m.p.: 206-208° C.

NMR (CDCl₃) δ: 3.05(5 Hz), 5.96(2H,s), 6.03(2H,s), 6.23(1H,m),6.80-6.93(3H,m), 7.26(1H,d,J=8z), 7.56(1H,d,J=1.8 Hz),7.58(1H,d,J=8 Hz),8.24(1H,d,J=1.8 Hz).

IR(KBr): 1639, 1536, 1488, 1286, 1226,1058, 1037 cm⁻¹

Elemental analysis for C₂₀H₁₅NO₅ Calcd: C, 68.76%; H, 4.33%; N, 4.01%Found: C, 68.37%; H, 4.31%; N, 3.98%

EXAMPLE 16N,N-Dimethyl-9-(1,3,-benzodioxole-5-yl)-naphtho[1,2-d]-1,3,-dioxole-7-carboxamide

The title compound was produced in a similar manner to that in Example11, using 9-(1,3-benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid which was prepared in ReferenceExample 12 and conductin a condensation reaction with dimethylamine (50%aqueous solution).

m.p.: 160-161° C.

NMR (CDCl₃) δ: 3.11(6H,brs), 5.95(2H,s) 6..02(2H,s), 6.80-6.93 (3H,m),7.24(1H,d,J=8 Hz), 7.31(1H,d,J=1.6 Hz), 7.42(1H,d,J=8 Hz),7.85(1H,d,J=1.6 Hz).

IR(KBr): 1629, 1496, 1486, 1280, 1232, 1031, 1039 cm⁻¹

Elemental analysis for C₂₁H₁₇NO₅ Calcd: C, 69.41%; H, 4.72%; N, 3/85%Found: C, 68.99%; H, 4.73%; N, 3.86%

EXAMPLE 17 Ethyl2-[9-(1,3-benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxamido]acetate

9-(1,3-Benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid(200 mg) which was prepared in Reference Example 12 was suspended in THF(6 ml), followed by addition of DMF (1drop). Oxalyl chloride (0.1 ) wasdropwise added to the resulting mixture at room temperature, followed bybeing stirred for 1 hour. the resulting reaction mixuture wasconcentrated under reduced pressure to yield crude9-(1,3-benzoxole-5-yl)-naphtho[1,2-d]1,3-dioxole-7-carboxyl chloride.Sodium hydrogencarbonate (150 mg) was dissolved in water (1 ml),followed by addition of glycine ester hydrochloride (91 mg) and THF (2ml). To the resulting mixture was added dropwise a solution of the avoveacide chlordie in THF under ice-cooling. After being stirred for onehour, the resulting mixture was extracted with ethyl acetate. Theextract was washed with brine an 1N hydrochloric acid and dried overmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was recrystalized from methanol to yield the title compound (213mg).

m.p.P 171-173° C.

NMR (CDCl₃) δ: 1.33(3H,t,J=7 Hz), 4.28(2H,q,J7 Hz), 4.29(2H,d,J=5 Hz),5.97(2H,s), 6.03(2H,s), 6.76(1H,m), 6.82-6.93(3H,m), 7.25(1H,d,J=9 Hz),7.60(1H,d,J=9 Hz), 7.62(1H,d,J=1.8 Hz), 8.28(1H,d,J=8 Hz).

IR(KBr): 1745, 1664, 1527, 1280, 1236, 1214, 1203 cm⁻¹

Elemental Analysis for C₂₃H₁₉N)₇ Calcd: C, 65.56%; H, 4.54%; N, 3.32%Found: C, 65.19%; H, 4.59%; N, 3.31%

EXAMPLE 182-[9-(1,3-Benzodioxole-5yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxamido]aceticacid

Ethyl2-[9-(1,3,-benzodioxole-5yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxamido]acetate(200 mg), which was produced in Example 17, was dissolved in THF (10 )and methanol (5 ml), followed by addition of a 1N aqueous solution ofNaOH. The resulting mixture was stirred at room temperature for 2 hours.After the mixture was concentrated under reduced pressure, the residurewas dissolved in water. The resulting aqueous solution was washed withether. To the mixture was added in 1N HCl until it pH reached to about2, followed by extraction with ethyl acetate. The extract was washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure. The resulting residue was recrystalized from methanol to yieldthe title compound (163 mg).

m.p.: 255-257° C.

NMR (CDCl₃) δ: 4.29(2H,d,J=5 Hz), 5.94(2H,s), 6.01(2H,s),6.68-7.00(4H,m), 7.22(1H,d,J=9 Hz), 7.55(1H,d,J=9 Hz), 7.59(1H,brs),8.25(1H,brs).

IR(KBr): 1720, 1625, 1529, 1429, 1282, 1235, 1056 cm⁻¹

Elemental Analysis for C₂₃H₁₅NO₇. 1.5H₂O Calcd: C, 62.16%; H, 4.08%; N,3.15% Found: C, 62.22%; H, 4.24%; N, 3.37%

EXAMPLE 19 N-(3-Dimethylaminopropyl)-9-(1,3-benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxamide hydrochloride

9-(1,3,-Benzodioxole-5-yl)-naphtho[1,2,-d]-1,3,-dioxole-7-carboxylicacid (200 mg), which was prepared in Reference Example 12, was suspendedin THF (6 ml), followed by addition of DMF (1 drop). Oxalychlordie (0.1ml) was added dropwise to the mixture. The resulting mixture was stirredfor one hour and concentrated under reduced pressure to yield crudenaphthalene-7-carboxyl cholride.

A solution of the above produced acide chloride in THF (6 ml) was addeddropwise to a solution of N,N-dimethylpropylenediamine (0.16 ml) in THF(2 ml). The mixture was stirred for 1 hour and, after addition of water,extracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified with column chromatography (silica-gel 10 g.eluent:chloroform-menthanol-aqueous ammonia=20:1:0.1 ) to yield its freeamine (about 240 mg.). This was dissolved in ethyl acetate (2 ml),followed by addition of 4N HCl-ethyl acetate (0.2 ml). The resultingprecipitates were collected by suction and recrystalized from ethanol toyield the title compound (166 mg).

m.p.: 233-240 ° C.

NMR (DMSO-d₆) δ: 1.84-2.02 (2H,m), 2.75(6H,s), 3.02-3.15(2H,m),3.30-3.45(2H,m), 6.02(2H,s) 6.09(2H,s), 6.90(1H,dd,J=1.6Hz,8 Hz),6.97(1H,dJ=8 Hz), 7.01(1H,d,J=1.6 Hz) 7.45(1H,d,J=9 Hz), 7.71(1H,d,J=1.8Hz), 7.75(1H,d,J=9 Hz), 8.45(1H,d,J=1.8 Hz), 8.82(1H,m).

IR(KBr): 1646,1535, 1488, 1291, 1232, 1038 cm⁻¹

Elemental Analysis for C₂₄H₂₅ClN₂O₅ Calcd: C, 63.09%; H, 5.51%; N, 6.13%Found: C, 62/85%; H, 5.44%; N, 6.10%

EXAMPLE 20 N-(3-Dimethylaminoethyl)-9-(1,3-benzodioxole-5yl)-naptho[1,2-d]-1,3,-dioxole-7-carboxamide hydrochloride

The title compound was produced in a similar manner to that in Example19, using 9-(1,3-benzodioxole-5-yl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid which was prepared in ReferenceExample 12 and conducting a condensation reaction withN,N-dimethylethylenediamine.

m.p.: 245-250° c.

NMR (DMSO-d₆) δ: 2.83(6H,s), 3.20-3.40(2H,m), 3.55-3.75(2H,m),6.02(2H,s), 6.09(2H,s), 6.09(2H,s), 6.90(1H,dd,J=1.4HZ,8hz),6.98(1H,d,J=8 Hz), 7.01(1H,d,J=1.4 Hz), 7.47(1H,d,J=1.6 Hz), 8.91(1H,m).

IR(KRr): 1648, 1544, 1500, 1488, 1288, 1232, 1039 cm⁻¹

Elemental Analysis for C₂₃H₂₃ClN₂O₅ Calcd: C, 62.37%; H, 5.23%; N, 6:33%Found: C, 62.12%; H, 5.20%; N, 6.41%

EXAMPLE 219-(1,3-Benzodioxole-5-yl)-8-methyl-naptho[1,2-d]-1,3,-dioxole-7-carboxamide

WSC[1-Ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride](33 mg)and ammonia (3N ethanol solution:0.14 ml) were added under ice-coolingto a DMF solution of9-(1,3-benzodioxole-5yl)-8-methyl-naphtho[1,2-d]-1,3,-dioxole-7-carboxylicacid (50 mg) which was prepared in Reference Example 13. The mixture wasstirred at room temperature for 2 hours, and the reaction was stoppedwith addition of water. The residue was purified with columnchromatography (Silica-Gel 5 g, eluent:ethyl acetate-hexane=1:1) andrecrystalized from methanol to yield the title compound (23 g).

m.p.: 244-246° C.

NMR (CDCl₃) δ: 2.41(3H,s), 5.82(1H,d,J=1.6Hz), 5.83(1H,d,J=1.6 Hz),6.03(1H,dJ=1.4 Hz), 6.06(1H,d,J=1.4 Hz), 6.68 (1H,dd,J=1.6Hz,8 Hz),6.73(1H,d,J=1.6 Hz), 6.87(1H,d,J=8 Hz), 7.18(1H,d,J=8 Hz), 7.53(1H,d,J=8Hz), 8.55(1H,s).

IR(KBr): 1677, 1486, 1438, 1272, 1091, 1039 cm⁻¹

EXAMPLE 229-(1,3-Benzodioxole-5-yl)-8-methyl-1,3-dioxole[4,4-f]quinoline-7-carboxamide

9-(1,3-Benzodioxole-5-yl)-8-methyl-1,3-dioxole[4,5-f]quinoline-7-carboxylicacid (150 mg), which was produced in Reference Example 14, was dissolvedin a mixture of THF (20 ml) and DMF (2 drops), followed by dropwiseaddition of oxalyl chloride (75 μl.) The reaction mixture was stirred atroom temperature one hour, and the solvent was distilled off underreduced pressure. The residue was dissolved in THF (20 ml) and addedslowly to 28% aqueous ammonia solution. After being stirred at roomtemperature for 1 hour, the mixture was concentrated under reducedpressure. The residue was dissolved in THF (20). The solution was addedgradually to 28% aqueous ammonia solution (50 ml) and stirred at roomtemperature for 10 minutes. The resulting product was extracted withethyl acetate. The extract was washed with water, dried over magnesiumsulfate and distilled to evaporate the solvent to yield the titlecompound as yellow crystals (135 mg). Some portions of the crudecrystals were recrystalized from THF-ethyl acetate for elementalanalysis and instrumental analysis.

m.p.: 214-216° C.

NMR (CDCl₃) δ: 2.50(3H,s) 5.68(1H,brs), 6.05(2H,m), 6.67(2H,m),6.88(1H,d,J=8 Hz), 7.34(1H,d,J=8 Hz), 7.69(1H,d,J=9 Hz), 7.84(1H,brs).

Elemental Analysis for C₁₉H₁₄N₂)₅ Calcd: C, 65.14%; H, 4.03%; N, 8.00%Found: C, 64.84%; H,,3.92%; N, 7.76%

EXAMPLE 23 N-methyl-9-(1,3-benzodioxole-5yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

9-(1,3-Benzodioxole-5-yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid (150 mg), which was produced in Reference Example 14, was dissovedin a mixture or THF (20 ml) and DMF (2drops), followed by addition ofoxalyl chloride (75 μl). The reaction mixture was stirred at roomtemperature for one hour and concentrated under reduced pressure. Theresidue was dissolved in THF (20 ml), the solution was added dropwise tomethylamine (40% methanol solution: 20 ml). The mixture was stirred atroom temperature for ten minutes. The product was extracted with ethylacetate. The extract was washed with water, dried over magnesium sulfateand concentrated under reduced pressure to yield the title compound asyellow crystals (61 mg). Some portions of the crude crystals wererecrystallized from THF-ethyl acetate for use for elemental analysis andinstrumental analysis.

m.p.: 141-146° C.

NMR (CDCl₃) δ: 2.50(3H,s), 3.05(3H,d,J=5Hz), 5.87(1H,brs), 6.05(2H,m),6.67(2H,m), 6.88(1H,d,J=8Hz), 7.34(1H,d,J=9Hz), 7.67(1H,d,J=9 Hz),7.90(1H,brs).

Elemental Analysis for C₂₀H₁₆N₂O₅ Calcd : C, 65.93%; H, 4.43%; N, 7.69%Found : C, 65.67%; H, 4.24%; N, 7.53%

EXAMPLE 24N-Methyl-9-(4-trifluoromethoxyphenyl)-8-hydroxymethylnaphtho[1,2-d]-1,3-dioxol-7-carboxamide

Using10-(4-trifluoromethoxyphenyl)-fro[3′,4′:6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-oneas obtained in Reference Example 15, the title compound was obtained inthe same manner as in Example 1.

m.p.: 195-197° C. (recrystallized from ethyl acetate-isopropyl ether)

NMR (CDCl₃) δ: 1.76(1H,brs), 3.09 (3H,d,J=4,6Hz), 4.35(2H,s),5.78(2H,s), 6.37(1H, brs), 7.20-7.40(5H,m), 7.47(1H,d,J=8.4Hz),7.97(1H,s).

IR (KBr): 32,97, 1634, 1254 cm⁻¹

Elemental analysis for C₂₁H₁₆F₃NO₅ Calcd : C, 60.15%; H, 3.85%; N, 3.34%Found : C, 60.01%; H, 3.96%; N, 3.40%

EXAMPLE 259-(4-Trifluoromethoxyphenyl)naphtho[1,2-d]-1,3-dioxol-7-carboxamide

Using9-(4-trifluoromethoxyphenyl)-naphtho[1,2-di]-1,3-dioxol-7-carboxylicacid as obtained in Reference Example 16, the title compound wasobtained in the same manner as in Example 11.

m.p.: 188-190° C. (recrystallized from ethyl acetate-isopropyl ether)

NMR (CDCl₃) δ: 5.60-6.20(2H,brs), 5.94(2H,s), 7.20-7.34(3H,m),7.46(2H,d,J=8.8Hz), 7.60-7.66(2H,m,), 8.32(1H,d,J=1.4Hz).

IR (KRr): 1632, 1466, 1292 cm⁻¹

Elemental analysis for C₁₉H₁₂F₃NO₄ Calcd : C, 60.81%; H, 3.22%; N, 3.73%Found : C, 60.74%; H, 3.34%; N, 3.69%

EXAMPLE 26N-Methyl-4-(1,3-benzodioxol-5-yl)-6.7-diethoxy-3-hydroxymethyl-naphthalene-2-carboxamide

Using 4-(1,3-benzodioxol-5-yl)-6.7-diethoxynaphtho[2,3-c]furan-1(3H)-oneas obtained in Reference Example 17, the title compound was obtained inthe same manner as in Example 1.

NMR (CDCl₃) δ: 1.41(3H,t,J=7Hz), 1.54(3H, t,J=7Hz), 3.08(3H,d,J=5Hz),3.94(2H,q,J=7Hz), 4.30-4.50(2H,m), 6.03(1H,d,J=1.4Hz),6.09(1H,d,J=1.4Hz), 6.42(1H,m), 6.75-6.90(3H,m), 6.95)(1H,d,J=8Hz),7.13(1H,s), 7.85(1H,s).

EXAMPLE 27N-Methyl-9=(4-trifluoromethoxyphenyl)-8-hydroxymethyl-1,3dioxolo[4,5-f]quinoline-7-carboxamide

Using10-(4-trifluoromethoxyphenyl)-1,3-dioxolo[4,5-f]fro[3,4-b]quinolin-7(9H)-oneas obtained in Reference Example 18, the title compound was obtained inthe same manner as in Example 1.

NMR (CDCl₃) δ: 3.12(3H,d,J=5Hz), 4.57(2H,d,J=8Hz), 5.30(1H,t,J=8Hz),5.87(1H,s), 7.25-7.40(3H,m), 7.43(1H,d,J=9Hz), 7.75(1H,d,J=9Hz),8.28(1H,m)

EXAMPLE 28N-Methyl-4-(1,3-benzodioxol-5-yl)-3-hydroxymethyl-6-methoxyquinoline-carboxamide

Using5-(1,3-benzodioxol-5-yl)-7-methoxyfro[4,5-f]fro[3,4-b]quinolin-2(4H)oneas obtained in Reference Example 19, the title compound was obtained inthe same manner as in Example 1.

NMR (CDCl₃) δ: 3.12(3H,d,J=5Hz), 3.77(3H,s), 4.67(2H,d,J=8Hz),5.39(1H,t,J=8Hz), 6.06(1H,d,J=1.4Hz), 6.11(1H,d,J=1.4Hz),6.75-7.00(4H,m), 7.38(1H,dd,J=3,9Hz), 7.99(1H,d,J=9Hz), 8.48(1H,m).

EXAMPLE 298-(1,3-Benzodioxol-5-yl)naphtho[2,3-d]-1,3-dioxol-6-carboxamide

Using 8-(1,3-benzodioxol-5-yl)-naphtho[2,3-d]-1,3-dioxol-6-carboxylicacid as obtained in Reference Example 20, the title compound wasobtained in the same manner as in Example 11.

NMR (CDCl₃) δ: 5.90-6.20(2H,m), 6.06(2H,s), 6.07(2H,s), 6.85-7.00(3H,m),7.22(1H,s), 7.24(1H,s), 7.60(1H,d,J=1.9Hz), 8.18(1H,d,J=1.9Hz).

EXAMPLE 30N-Methyl-8-(1,3-benzodioxol-5-yl)naphtho[2,3-d]-1,3-dioxol-6-carboxamide

NMR (CDCl₃) δ: 3.05(3H,d,J=7Hz), 6.05(4H,s), 6.25(1H,m),6.80-7.00(3H,m), 7.20(1H,s), 7.22(1H,s). 7.55(1H,d,J=1.9Hz),8.12(1H,d,J=1.9Hz).

EXAMPLE 316-Chloro-4-(4-chlorophenyl)-3-hydroxymethyl-N-methyl-naphthalene-2-carboxamide

Using 6-chloro-4-(4-chlorophenyl)naphtho[2,3-c]furan-1(3H)-one asobtained in Reference Example 21, the title compound was obtained in thesame manner as in Example 1.

m.p.: 160° C. (decomp.) (recrystallized from THF)

NMR (CDCl₃) δ: 3.09(3H,d,J=4.8Hz), 4.39(2H,s), 6.49(1H,brs),7.28(2H,d,J=8.4Hz), 7.39(1H,m), 7.34(1H,m), 7.51(2H,d,J=8.4Hz),7.81(1H,d,J=8.4Hz), 8.00(1H,s).

IR (KBr): 3285, 3083, 2942, 2876, 1634, 1555, 1483 cm⁻¹

EXAMPLE 324-(4-Fluorophenyl)-3-(2-hydroxymethyl)-6-methoxy-N-methyl-2-carboxamide

Using5-(4-fluorophenyl)-3,4-dihydro-7-methoxy-1H-pyrano[3,4-b]quinolin-1-oneas obtained in Reference Example 22, the title compound was obtained inthe same manner as in Example 1.

m.p.: 139-140° C. (recrystallized from ethyl acetate-THF)

NMR (CDCl₃) δ: 3.09(3H,d,J=5.0Hz), 3.25(2H,t,J=6.0Hz), 3.69(3H,s),3.69(2H,m), 4.52(1H,m), 6.44(1H,d,J=2.4Hz), 7.25(4H,m),7.35(1H,dd,J=9.2,2.4Hz), 7.98(1H,d,J=9.2Hz), 8.19(1H,brs).

IR (KBr): 3316, 2942, 1651, 1618, 1493 cm⁻¹

Elemental analysis for C₁₉H₁₄FNO₃ Calcd : C, 70.58%; H, 4.36%; N, 4.33%Found : C, 70.49%; H, 4.57%; N, 4.26%

EXAMPLE 339-(1,3-Benzodioxol-5-yl)-8-(2-hydroxyethyl)-N-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using11-(1,3-benzodioxol-5-yl)-9,10-dihydro-7H-1,3-dioxolo[4,5-f]pyrano[3,4-b]quinolin-7-oneas obtained in Reference Example 23, the title compound was obtained inthe same manner as in Example 1.

NMR (CDCl₃) δ: 3.07 (3H,d,J=5.2Hz), 3.1-3.3(2H,m), 3.71(2H,t,J=6.2Hz),5.87(1H,d,J=1.4Hz), 5.87(1H,d,J=1.4Hz), 6.04(1H,d,J=1.4Hz),6.07(1H,d,J=1.4Hz), 6.65-6.75(2H,m), 6.86(1H,d,J=7.8Hz),7.37(1H,d,J=8.8Hz), 7.69(1H,d,J=8.8Hz), 8.10(1H,m).

EXAMPLE 349-(1,3-Benzodioxol-5-yl)-N-methyl-8-methylaminocarboxymethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

A mixture of9-(1,3-benzodioxol-5-yl)-8-ethoxycarbonylmethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid ethyl ester as obtained in Reference Example 23 (a) (106 mg), a 40%methylamine-methanol solution (5 ml) and THF (5 ml) was heated at 140°C. in a sealed tube for 2 hours. After cooling, the reaction mixture wasdiluted with water and extracted with ethyl acetate. After being washedwith brine, the extract was dried with magnesium sulfate; the solventwas distilled off under reduced pressure. After the insoluble substanceswere filtered off, the product was treated with isopropyl ether to yieldthe title compound as a pale yellow crystal (4.6 mg).

NMR (CDCl₃) δ: 2.75(3H,d,J=4.8Hz), 3.03(3H,d,J=5.2Hz), 3.9-4.1(2H,m),5.02(1H,m), 5.86(1H,d,J=1.4Hz), 5.88(1H,d,J=1.4Hz), 6.01(1H,d,J=1.4Hz),6.05(1H,d,J=1.4Hz), 6.73(1H,dd,J=7.8,1.6Hz), 6.78(1H,d,J=1.6Hz),6.86(1H,d,J=7.8Hz), 7.38(1H,d,J=8.8Hz), 7.70(1H,d,J=8.8Hz), 8.13(1H,m).

EXAMPLE 35 6-Chloro-4-(4-pyridyl)-2-quinolinecarboxamide

Using 6-chloro-4-(4-pyridyl)-2-quinolinecarboxylic acid as obtained inReference Example 24, the title compound was obtained in the same manneras in Example 11.

NMR (CDCl₃) δ: 7.65(2H,dd,J=4.4,1.4Hz), 7.81(1H,d,J=2.2Hz),7.92(1H,brs), 7.95(1H,dd,J=8.8,2.2Hz), 8.09(1H,s), 8.24(1H,d,J=8.8Hz),8.40(1H,brs), 8.81(2H,dd,J=4.4,1.4Hz).

Elemental analysis for C₁₅H₁₀N₃OCl Calcd : C, 63.50%; H, 3.55%; N,14.81% Found : C, 63.38%; H, 3.62%; N, 14.75%

EXAMPLE 36 6-Chloro-N-methyl-4-(4-pyridyl)-2-quinolinecarboxamide

Using 6-chloro-4-(4-pyridyl)-2-quinolinecarboxylic acid as obtained inReference Example 24, the title compound was obtained in the same manneras in Example 11.

NMR (CDCl₃) δ: 3.13(3H,d,J=5.2Hz), 7.45(2H,dd,J=4.4,1.4Hz),7.75(1H,dd,J=8.8,2.2Hz), 7.83(1H,d,J=2.2Hz), 8.13(1H,d,J=8.8Hz),8.19(1H,m), 8.29(1H,s), 8.84(2H,dd,J=4.4,1.6Hz).

Elemental analysis for C₁₆H₁₂N₃OCl Calcd : C, 64.54%; H, 4.06%; N,14.11% Found : C, 64.55%; H, 4.09%; N, 14.06%

EXAMPLE 376-Chloro-N-(4-methoxyphenyl)-4-(4-pyridyl)-2-quinolinecarboxamide

Using 6-chloro-4-(4-pyridyl)-2-quinolinecarboxylic acid as obtained inReference Example 24, the title compound was obtained in the same manneras in Example 11.

NMR (CDCl₃) δ: 3.82(3H,s), 4.69(2H,d,J=5.8Hz), 6.91(2H,d,J=8.8Hz),7.36(2H,d,J=8.8Hz), 7.45(2H,dd,J=4.4,1.8Hz), 7.73(1H,dd,J=8.8,2.2Hz),7.83(1H,d,J=2.2Hz), 8.11(1H,d,J=8.8Hz), 8.32(1H,s), 8.47(1H,m),8.84(2H,dd,J=4.4,1.8Hz).

Elemental analysis for C₂₈H₁₈N₃O₂Cl•¼H₂O Calcd : C, 67.65%; H, 4.57%; N,10.29% Found : C, 67.71%; H, 4.67%; N, 10.23%

EXAMPLE 38 9-(4-Methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 25, the title compound was obtained inthe same manner as in Example 11.

NMR (CDCl₃) δ: 3.89(3H,s), 5.70(1H,brs), 6.02(2H,s), 6.89(2H,d,J=8.8Hz),7.43(2H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz), 7.82(1H,d,J=8.8Hz), 8.00(1H,s).

EXAMPLE 399-(4-Methoxyphenyl)-N-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 25, the title compound was obtained inthe same manner as in Example 11.

NMR (CDCl₃) δ: 3.10(3H,d,J=5.2Hz), 3.89(3H,s), 6.00(2H,s),6.98(2H,d,J=8.8Hz), 7.43(2H,d,J=8.8Hz), 7.45(1H,d,J=8.8Hz),7.79(1H,d,J=8.8Hz), 8.10(1H,s), 8.17(1H,m).

EXAMPLE 409(4-Methoxyphenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 25, the title compound was obtained inthe same manner as in Example 11.

NMR (CDCl₃) δ: 3.81(3H,s), 3.89(3H,s), 4.66(2H,d,J=5.8Hz), 6.00(2H,s),6.90(2H,d,J=8.8Hz), 6.98(2H,d,J=8.4Hz), 7.3-7.5(5H,m),7.76(1H,d,J=8.8Hz), 8.13(1H,s), 8.44(1H,m).

EXAMPLE 419-(1,3-Benzodioxol-5-yl)-N,N-dimethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid as obtained in Reference Example 26, the title compound wasobtained in the same manner as in Example 11.

NMR (CDCl₃) δ: 3.18(3H,s), 3.21(3H,s), 6.00(2H,s), 6.83-6.98(3H,m),7.22(1H,d,J=9.0Hz), 7.51(1H,s), 7.78(1H,d,J=9.0Hz).

Elemental analysis for C₂₀H₁₆N₂O₅ Calcd : C, 65.93%; H, 4.43%; N, 7.69%Found : C, 65.71%; H, 4.34%; N, 7.59%

EXAMPLE 429-(1,3-Benzodioxol-5-yl)-N-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid as obtained in Reference Example 26, the title compound wasobtained in the same manner as in Example 11.

NMR (CDCl₃) δ: 3.08(3H,d,J=5.2Hz), 5.99(2H,s), 6.01(2H,s),6.83-7.00(3H,m), 7.39(1H,d,J=8.8Hz), 7.74(1H,d,J=8.8Hz), 8.07(1H,s),8.21 1H,brd,J=4.8Hz).

EXAMPLE 439-(1,3-Benzodioxol-5-yl)-N-propyl-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid as obtained in Reference Example 26, the title compound wasobtained in the same manner as in Example 11.

NMR (CDCl₃) δ: 1.03(3H,t,J=7.6Hz), 1.71(2H,q,J=7.2Hz),3.49(2H,q,J=7.0Hz), 6.02(2H,s), 6.03(2H,s), 6.84-7.00(3H,m),7.43(1H,d,J=8.8Hz), 7.79(1H,d,J=8.8Hz), 8.08(1H,s), 8.23(1H,brs).

Elemental analysis for C₂₁H₁₆N₂O₅•0.3H₂O Calcd : C, 65.72% H, 4.88%; N,7.30% Found : C, 65.70% H, 5.08%; N, 7.06%

EXAMPLE 449-(1,3-Benzodioxol-5-yl)-N-(4-methoxyphenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid as obtained in Reference Example 26, the title compound wasobtained in the same manner as in Example 11.

NMR (CDCl₃) δ: 3.84(3H,s), 6.06(4H,s), 6.87-7.03(5H,m), 7.30(1H,s),7.50(1H,d,J=8.8Hz), 7.76(2H,d,J=9.2Hz), 7.91(1H,d,J=8.8Hz), 8.18(1H,s).

Elemental analysis for C₂₅H₁₈N₂O₆•0.2H₂O Calcd : C, 67.32%; H, 4.15%; N,6.28% Found : C, 67.21%; H, 4.11%; N, 6.25%

EXAMPLE 459-(1,3-Benzodioxol-5-yl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylicacid as obtained in Reference Example 26, the title compound wasobtained is the same manner as in Example 11.

NMR (CDCl₃) δ: 3.81(3H,s), 4.67(2H,d,J=5.8Hz), 6.03(2H,s), 6.05(2H,s),6.80-7.08(5H,m), 7.35(2H,d,J=8.8Hz), 7.43(1H,d,J=9.2Hz), 7.76(1H,d,J=9.2Hz), 8.12(1H,s), 8.43(1H,brs).

Elemental analysis for C₂₆H₂₀N₂O₆•0.1H₂O Calcd : C, 68.15%; H, 4.44%; N,6.11%; Found : C, 68.0%4; H, 4.70%; N, 6.20%

EXAMPLE 469-(4-Fluorophenyl)-N-methyl-1,3-dioxolo[4,5-F]quinoline-7-carboxamide

Using 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 27, the title compound was obtained inthe same manner as in Example 11.

m.p.: 233-235° C.

NMR (CDCl₃) δ: 3.10(3H,d,J=5.2Hz), 6.00(2H,s), 7.08-7.20(2H,m),7.40-7.50(3H,m), 7.80(1H,d,J=9.0Hz), 8.10(1H,s), 8.16(1H,brs).

Elemental analysis for C₁₈H₁₃N₂O₃F•0.1H₂O Calcd : C, 66.30%; H, 4.08%;N, 8.59% Found : C, 66.11%; H, 4.14%; N, 8.59%

EXAMPLE 479-(4-Fluorophenyl)-N-[(4-methoxyphenyl)methyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 27, the title compound was obtained inthe same manner as in Example 11.

m.p.: 171-173° C.

NMR (CDCl₃) δ: 3.81(3H,s), 4.67(2H,d,J=6.2Hz), 5.99(2H,s),6.90(2H,d,J=8.4Hz), 7.06-7.22(2H,m), 7.35(2H,d,J=8.4Hz),7.40-7.55(3H,m), 7.77(1H,d,J=8.8Hz), 8.12(1H,s), 8.44(1H,s).

Elemental analysis for C₂₃H₁₉N₂O₄F•0.1H₂O Calcd : C, 69.47%; H, 4.47%;N, 6.48% Found : C, 69.31%; H, 4.51%; N, 6.45%

EXAMPLE 48N-Benzyl-N-[9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carbonyl]piperazine

Using 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 27, the title compound was obtained inthe same manner as in Example 11.

m.p.: 147-148° C.

NMR (CDCl₃) δ: 2.50(2H, t, J=4.8 Hz), 2.59(2H, t, J=4.8 Hz), 3.77(2H, t,J=4.8 Hz), 3.88(2H, t, J=4.8 Hz), 5.96(2H, s), 7.02-7.20(2H, m),7.20-7.38(5H, m), 7.38-7.50(3H, m), 7.52(1H, s), 7.78(1H, d, J=9.2 Hz).

Elemental analysis for C₂₈H₂₄N₃O₃F Calcd: C, 71.63%; H, 5.15%; N, 8.95%.Found: C, 71.56%; H, 5.17%; N, 8.94%.

EXAMPLE 499-(4-Fluorophenyl)-N-[2-(4-methoxyphenyl)ethyl]-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 27, the title compound was obtained inthe same manner as in Example 11.

NMR (CDCl₃) δ: 2.94(2H, t, J=6.8 Hz), 3.66-3.82(2H, m), 3.81(3H, s),5.99(2H, s), 6.89(2H, d, J=8.8 Hz), 7.06-7.30(4H, m), 7.43(1H, d, J=8.8Hz), 7.46(2H, d, J=8.8 Hz), 7.77(1H, d, J=8.8 Hz), 8.09(1H, s), 8.26(1H,brs).

Elemental analysis for C₂₆H₂₁N₂O₄F Calcd: C, 70.26%; H, 4.76%; N, 6.30%.Found: C, 70.19%; H, 4.83%; N, 6.29%.

EXAMPLE 50N-[2-[4-(Acetylamino)phenyl]ethyl]-9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 27, the title compound was obtained inthe same manner as in Example 11.

NMR (CDCl₃) δ: 2.18(3H, s), 2.96(2H, t, J=6.6 Hz), 3.70-3.80(2H, m),6.00(2H, s), 7.00-7.35(5H, m), 7.35-7.60(4H, m), 7.78(1H, d, J=8.8 Hz),8.08(1H, s), 8.27(1H, brs).

EXAMPLE 519-(4-Fluorophenyl)-N-(2-hydroxyethyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxamide

Using 9-(4-fluorophenyl)-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acidas obtained in Reference Example 27, the title compound was obtained inthe same manner as in Example 11.

NMR (CDCl₃) δ: 2.88(1H, brs), 3.65-3.80(2H, m), 3.90(2H, brs), 6.00(2H,s), 7.05-7.20(2H, m), 7.38-7.52(3H, m), 7.81(1H, d, J=8.8 Hz), 8.07(1H,s), 8.55(1H, brs).

EXAMPLE 523-Dimethylaminomethyl-6-methoxy-4-(4-methoxyphenyl)-N-methyl-2-quinolinecarboxamide

After a mixture of3-bromomethyl-6-methoxy-4-(4-methoxyphenyl)quinoline-2-carboxylic acidmethyl ester (152 mg), a 50% aqueous solution of dimethylamine (0.5 ml)and methanol (5 ml) was stirred at room temperature for 2 hours, waterwas added to the reaction mixture, followed by extraction with ethylacetate. After being washed with brine, the extract was dried overmagnesium sulfate; the solvent was distilled off under reduced pressure.To the residue, THF (5 ml) and a 40% methylamine-methanol solution (5ml) was added, followed by refluxing for 16 hours, after which thesolvent was distilled off under reduced pressure to yield the titlecompound as a colorless powder (26 mg).

NMR (CDCl₃) δ: 2.06(6H, s), 2.78(3H, d, J=5.2 Hz), 3.70(3H, s), 3.72(2H,m), 3.93(3H, s), 6.66(1H, d, J=3.0 Hz), 7.05(2H, d, J=8.8 Hz), 7.16(2H,d, J=8.8 Hz), 7.34(1H, dd, J=9.0, 3.0 Hz), 8.01(1H, d, J=9.0 Hz),8.44(1H, m).

EXAMPLE 53N-Methyl-8-(1-piperidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxamide

After a mixture of ethyl8-(1-piperidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate as obtainedin Reference Example 31 (60 mg) and a 40% methylamine-methanol solution(5 ml) was stirred at room temperature for 3 hours, the solvent wasdistilled off under reduced pressure to yield the title compound as acolorless powder (33.6 mg).

NMR (CDCl₃) δ: 1.5-2.0(6H, m), 3.06(3H, d, J=4.8 Hz), 3.15(4H, m),6.11(2H, s), 7.27(1H, s), 7.30(1H, s), 7.71(1H, s), 8.18(1H, brs).

EXAMPLE 54N-Methyl-8-(1-pyrrolidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxamide

Using ethyl 8-(1-pyrrolidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylateas obtained in Reference Example 31, the title compound was obtained inthe same manner as in Example 53.

NMR (CDCl₃) δ: 2.03(4H, m), 3.05(3H, d, J=5.2 Hz), 3.68(4H, m), 6.08(2H,s), 7.23(1H, s), 7.39(1H, s), 7.53(1H, s), 8.20(1H, brs).

EXAMPLE 55N-Methyl-8-(4-morpholinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxamide

Using ethyl 8-(4-morpholinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylateas obtained in Reference Example 32, the title compound was obtained inthe same manner as in Example 53.

NMR (CDCl₃) δ: 3.07(3H, d, J=5.2 Hz), 3.21(4H, m), 3.97(4H, m), 6.13(2H,s), 7.31(2H, s), 7.75(1H, s), 8.17(1H, m).

EXAMPLE 56N-Methyl-8-(4-methylpiperazin-1-yl)-1,3-dioxolo[4,5-g]quinoline-6-carboxamide

Using ethyl8-(4-methylpiperazin-1-yl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate asobtained in Reference Example 33, the title compound was obtained in thesame manner as in Example 53.

NMR (CDCl₃) δ: 2.41(3H, s), 2.69(4H, m), 3.07(3H, d, J=5.2 Hz), 3.25(4H,m), 6.12(2H, s), 7.29(2H, s), 7.74(1H, s), 8.17(1H, m).

EXPERIMENTAL EXAMPLE 1 Induction of Alkaline Phosphatase (ALP)Production in Mouse Osteoblastic Cells

Mouse-derived MC3T3-E1 osteoblast cells were seeded in a 96-wellmicrotiter plate of α-minimum essential medium containing FCS (fetalcalf serum) (8000 cells/well). After two days when the growth had becomeconfluent, the test substance diluted to various concentrations in Table1 with the medium either containing or not containing 3 ng/ml of BMP-4/7heterodimer (described in Japanese Patent Application No. 111255/1994)was added, and the microtiter plate was further incubated for 72 hours.The plate was washed once with a physiological saline solution, followedby addition of a substrate solution. The resulting mixture was incubatedat room temperature for 15 minutes, followed by addition of 0.05N NaOHto terminate the reaction. The absorbance at 405 nm was measured. Theresults as shown in Table 1 proved that the compounds of the presentinvention strengthen BMP activity, i.e. induction of ALP production byBMP and that those compounds themselves have excellent ALP productioninducing activity regardless of the presence or absence of BMP.

TABLE 1 Conc. of Example compound ALP Activity (1000 × A405 ± SD) No.(μM) BMP Addition BMP Non-Addition 1 1 386 ± 30* 102 ± 5* 0.1 213 ± 5*  58 ± 5* 0.01 193 ± 15  50 ± 5 0 (control) 173 ± 9  42 ± 5 2 1 478 ± 17* 162 ± 18* 0.1 354 ± 15*  95 ± 7* 0.01 323 ± 13  80 ± 2 0 (control) 268± 18  73 ± 4 4 1 554 ± 49* 168 ± 4* 0.1 389 ± 25* 108 ± 7* 0.01 301 ± 8 86 ± 3 0 (control) 303 ± 11  78 ± 6 5 1 431 ± 26*  157 ± 11* 0.1 237 ±14*  62 ± 3* 0.01 170 ± 20  49 ± 1 0 (control) 171 ± 6  48 ± 3 6 1 459 ±35* 168 ± 1* 0.1 248 ± 6*   74 ± 1* 0.01 177 ± 14  51 ± 2 0 (control)165 ± 9  46 ± 5 8 1 570 ± 63* 186 ± 26 0.1 477 ± 15* 134 ± 12 0.01 426 ±28  105 ± 22 0 (control) 395 ± 1  146 ± 49 22 1 326 ± 18*  190 ± 10* 0.1226 ± 6*   149 ± 11* 0.01 187 ± 3  135 ± 8* 0 (control) 182 ± 9  119 ±5  *p < 0.05 vs control; t-test

FORMULATION EXAMPLE 1

About 1,000 uncoated tablets measuring 6.5 mm in diameter and containing5 mg of the compound of Example 1 can be prepared by mixing thefollowing components (1)-(6) and compressing the mixture with a tabletmachine. Film-coated tablets each measuring 6.6 mm in diameter can beobtained by coating those tablets with the following components (7)-(9).

(1) Compound of Example 5 g (2) Lactose 82.5 g (3)Hydroxypropylcellulose 2.8 g (4) Magnesium stearate 0.4 g (5)Hydroxypropylmethylcellulose 2910 2.994 g (6) Corn starch 19.3 g (7)Macrogol 6000 0.6 g (8) Titanium oxide 0.4 g (9) Iron sesquioxide 0.006g

FORMULATION EXAMPLE 2

Uncoated granules can be prepared by suspending or dissolving thefollowing components (1), (2), (3), (4), (5), (6), (7) and (8) inpurified water and coating a granular core material (2) with thesuspension or solution. About 500 mg of 1% fine granules of the compoundof Example 1 can be prepared by coating the uncoated granules with thecomponents (9)-(11) to prepare fine granules and mixing with thefollowing component (12). The fine granule are dispensed in packets in500 mg per packet.

(1) Compound of Example 5 g (2) Lactose-crystalline cellulose (granule)330 g (3) D-mannotp 29 g (4) Low-substituted hydroxypropylcellulose 20 g(6) Talc 25 g (6) Hydroxypropylcellulose 50 g (7) Aspartame 3 g (8)Dipotassium glycyrrhizinate 3 g (9) Hydroxypropylmethylcellulose 2910 30g (10)  Titanium oxide 3.5 g (11)  Yellow iron sesquioxide 0.5 g (12) Light silicic anyhydride 1 g

INDUSTRIAL APPLICABILITY

The cell differentiation inducing composition or the celldifferentiation factor activity enhancing composition containing thecompound [I] or a salt thereof has high BMP (bone morphogeneticprotein)-like activity or enhances BMP activity and increases bone massand strength by acting upon bone tissues. Therefore, the composition ofthe present invention is useful for the treatment or prevention of bonediseases such as osteoporosis and the acceleration of bone fracturehealing or bone remodeling. This composition also has neurotrophicfactor-like activity or enhances neurotrophic factor activity.Therefore, the composition is useful for the treatment or prevention ofvarious nerve diseases such as Alzheimer's disease, senile dementia,Perkinson disease, motor neuronal diseases (e.g., amyotrophic lateralsclerosis) and diabetic peripheral neuropathy.

What is claimed is:
 1. A compound represented by the formula:

wherein R¹ is an amino group which may be substituted by (a) a C₁₋₆alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may be substitutedby a group selected from the group consisting of (i) a halogen atom,(ii) C₁₋₃ alkylenedioxy, (iii)nitro, (iv) cyano, (v) optionallyhalogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii)optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix)optionally halogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino,(xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acylamino selected from C₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xvii) C₆₋₁₀aryloxy, (b) a hydroxy group which may be substituted by a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may be substituted by agroup selected from the group consisting of (i) a halogen atom, (ii)C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenatedC₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy, or (c) anamino group which may be substituted by an acyl group represented by anyone of the formula: —(C═O)—R⁷, —SO₂—R⁷, —(C═O)NR⁸R⁷, —(C═O)O—R⁷,—(C═S)O—R⁷ or —(C═S)NR⁸R⁷ wherein R⁷ is (a) hydrogen atom or (b) a C₁₋₆alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may be substitutedby a group selected from the group consisting of (i) a halogen atom,(ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionallyhalogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii)optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix)optionally halogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino,(xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acylamino selected from C₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy, and R⁸ is hydrogen atom or a C₁₋₆ alkyl group, or (d) R¹ is agroup formed by removing a hydrogen atom from a nitrogen atom of a 5 to9 membered nitrogen-containing heterocycle which may have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,other than carbon atoms and one nitrogen atom, and thenitrogen-containing heterocycle may be substituted by a group selectedfrom the group consisting of (i) a halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy; R² is ahydrogen atom; X is a methyne group which may be substituted; a ring Ais a 4-10 membered homo-cycle which is substituted by a loweralkylenedioxy; and a ring B is a homo- or hetero-cycle which may besubstituted; or a pharmaceutically acceptable salt thereof.
 2. Thecompound as claimed in claim 1 wherein X is CR⁶ wherein R⁶ is (a) ahydrogen atom, (b) a halogen atom, (c) a C₁₋₆ alkyl group, C₂₋₆ alkenylgroup, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl group orC₇₋₁₆ aralkyl group which may be substituted by a group selected fromthe group consisting of (i) a halogen atom, (ii) C₁₋₃ alkylenedioxy,(iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi)optionally halogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionally halogenated C₁₋₆alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii)amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5or 6 membered cyclic amino, (xvi) acyl amino selected from C₁₋₆alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy or (d)—OR^(6″) is (a′) a hydrogen atom or (b′) a C₁₋₆ alkyl group, C₂₋₆alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group, C₆₋₁₄ arylgroup or C₇₋₁₆ aralkyl group which may be substituted by a groupselected from the group consisting of (i) a halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy; the ring Ais a 4 to 10 membered cyclic hydrocarbon which is substituted by C₁₋₃alkylenedioxy; and the ring B is a 3 to 10 membered cyclic hydrocarbonor 5 to 9 membered heterocycle containing 1 to 4 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom other than carbonatoms, and the 3 to 10 membered cyclic hydrocarbon or 5 to 9 memberedheterocycle may be substituted by a group selected from the groupconsisting of (i) a halogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro,(iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi) optionallyhalogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl,(viii) C₃₋₆ cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x)optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii)mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 memberedcyclic amino, (xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy.
 3. The compound as claimed in claim 1 wherein R¹ is a grouprepresented by the formula:

wherein R³ and R⁴ is the same or different and are independently ahydrogen atom, a hydroxy group which may be substituted, a lower alkylgroup which may be substituted, an acyl group, an aryl group which maybe substituted or an aralkyl group which may be substituted, or R³ andR⁴ may combine with an adjacent nitrogen atom and form anitrogen-containing heterocyclic group which may be substituted.
 4. Thecompound as claimed in claim 3 wherein R³ and R⁴ are the same ordifferent and are independently a hydrogen atom, a hydroxy group whichmay be substituted, a lower alkyl group which may be substituted or anacyl group, or R³ and R⁴ may combine with an adjacent nitrogen atom andform a nitrogen-containing heterocyclic group which may be substituted.5. The compound as claimed in claim 3 wherein R³ and R⁴ are the same ordifferent and are independently a hydrogen atom or a lower alkyl groupwhich may be substituted.
 6. The compound as claimed in claim 3 whereinR³ is a hydrogen atom or a C₁₋₆ alkyl group, and R⁴ is (i) a hydrogenatom or (ii) a C₁₋₆ alkyl group which may be substituted by a groupselected from the group consisting of hydroxy, carboxyl, C₁₋₆alkoxy-carbonyl, amino and mono- or d-C₁₋₆ alkyl amino, (iii) a C₆₋₁₄aryl group which may be substituted by C₁₋₆ alkoxy or (iv) a C₇₋₁₆aralkyl group which may be substituted by C₁₋₆ alkoxy or C₁₋₆ acylamino,or R³ and R⁴ combine with an adjacent nitrogen atom and form a 5 to 8membered nitrogen-containing heterocyclic group which may be substitutedby C₇₋₁₆ aralkyl.
 7. The compound as claimed in claim 1 wherein the ringA is a benzene ring which is substituted by a lower alkylenedioxy. 8.The compound as claimed in claim 1 wherein the ring A is a C₆₋₁₀aromatic hydrocarbon ring which is substituted by a C₁₋₃ alkylenedioxy.9. The compound as claimed in claim 1 wherein the ring B is a benzenering which may be substituted.
 10. The compound as claimed in claim 1wherein the ring B is (i) a C₆₋₁₂ aromatic hydrocarbon ring which may besubstituted by a group selected from the group consisting of a halogenatom, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆alkoxy and C₁₋₃ alkylenedioxy or (ii) a 5 to 8 membered heterocyclecontaining 1 to 3 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom other than carbon atoms, and the 5 to 8 memberedheterocycle may be substituted by C₁₋₆ alkyl.
 11. The compound asclaimed in claim 1 wherein R¹ is a group represented by the formula:

wherein R^(3′) is a hydrogen atom or a C₁₋₆ alkyl group, and R^(4′) is(i) a hydrogen atom, (ii) a C₁₋₆ alkyl group which may be substituted bya group selected from the group consisting of hydroxy, carboxyl, C₁₋₆alkoxy-carbonyl, amino and mono- or di-C₁₋₆ alkylamino, (iii) a C₆₋₁₄aryl group which may be substituted by C₁₋₆ alkoxy or (iv) a C₇₋₁₆aralkyl group which may be substituted by C₁₋₆ alkoxy or C₁₋₆ acylamino,or R^(3′) and R^(4′) may combine with an adjacent nitrogen atom and forma 5 to 8 membered nitrogen-containing heterocyclic group which may besubstituted by C₇₋₁₆ aralkyl; R² is a hydrogen atom; X is a methynegroup which may be substituted by C₁₋₆ alkyl; the ring A is a C₆₋₁₀aromatic hydrocarbon ring which is substituted by a C₁₋₃ alkylenedioxy;and the ring B is (i) a C₆₋₁₀ aromatic hydrocarbon ring which may besubstituted by a group selected from the group consisting of a halogenatom, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆alkoxy and C₁₋₃ alkylenedioxy or (ii) a 5 to 8 membered heterocyclecontaining 1 to 3 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom other than carbon atoms, and the 5 to 8 memberedheterocycle may be substituted by C₁₋₆ alkyl.
 12. The compound asclaimed in claim 1 wherein R¹ is a group represented by the formula:

wherein R^(3″) is a hydrogen atom and R^(4″) is a hydrogen atom or aC₇₋₁₆ aralkyl group which may be substituted by C₁₋₆ alkoxy; R² is ahydrogen atom; X is a methyne group; the ring A is a C₆₋₁₀ aromatichydrocarbon ring which is substituted by C₁₋₃ alkylenedioxy; and thering B is a C₆₋₁₀ aromatic hydrocarbon ring which may be substituted bya group selected from the group consisting of a halogen atom, C₁₋₆alkoxy and C₁₋₃ alkylenedioxy.
 13. A method for producing the compoundas claimed in claim 1 or a ester thereof, or a pharmaceuticallyacceptable salt thereof which comprises subjecting a compoundrepresented by the formula:

wherein each symbol is same as defined in claim 1, or a pharmaceuticallyacceptable salt thereof to an amidating reaction, and optionallyfollowed by an acylating reaction.
 14. A pharmaceutical compositionwhich comprises the compound as claimed in claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier orexcipient.
 15. A method for inducing cell differentiation or enhancinginduction of cell differentiation of a mammalian cell which comprisesadministering to said mammalian cell an effective amount of a compoundrepresented by the formula:

wherein a ring A′ is a 4-10 membered homo-cycle which is substituted bya lower alkylenedioxy; R¹ is an amino group which may be substituted by(a) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆cycloalkyl group, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₃ alkylenedioxy, (iii)nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) optionally halogenated C₁₋₆ alkoxy, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkyl amino, (xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclicamino, (xvi) acyl amino selected from C₁₋₆ alkoxy-carbonyl amino,mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xvii) C₆₋₁₀aryloxy, (b) a hydroxy group which may be substituted by a C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkyl group,C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may be substituted by agroup selected from the group consisting of (i) a halogen atom, (ii)C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenatedC₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy, or (c) anamino group which may be substituted by an acyl group represented by anyone of the formula: —(C═O)—R⁷, —SO₂—R⁷, —(C═O)NR⁸R⁷, —(C═O)O—R⁷,—(C═S)O—R⁷ or —(C═S)NR⁸R⁷ wherein R⁷ is (a) hydrogen atom or (b) a C₁₋₆alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₆ cycloalkylgroup, C₆₋₁₄ aryl group or C₇₋₁₆ aralkyl group, which may be substitutedby a group selected from the group consisting of (i) a halogen atom,(ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionallyhalogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii)optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix)optionally halogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino,(xiv) di-C₁₋₆ alkyl amino, (xv) 5 or 6 membered cyclic amino, (xvi) acylamino selected from C₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆alkylaminocarbonyl amino, C₁₋₆ alkylcarbonyl amino and C₁₋₆alkylsulfonyl amino, (xvii) C₁₋₆ alkylcarbonyl, (xviii) carboxyl, (xix)C₁₋₆ alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl,(xxii) di-C₁₋₆ alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv)sulfo, (xxv) C₁₋₆ alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀aryloxy, and R⁸ is hydrogen atom or a C₁₋₆ alkyl group, or (d) R¹ is agroup formed by removing a hydrogen atom from a nitrogen atom of a 5 to9 membered nitrogen-containing heterocycle which may have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,other than carbon atoms and one nitrogen atom, and thenitrogen-containing heterocycle may be substituted by a group selectedfrom the group consisting of (i) a halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) optionallyhalogenated C₁₋₆ alkoxy, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkyl amino, (xiv) di-C₁₋₆ alkylamino, (xv) 5 or 6 membered cyclic amino, (xvi) acyl amino selected fromC₁₋₆ alkoxy-carbonyl amino, mono-C₁₋₆ alkylaminocarbonyl amino, C₁₋₆alkylcarbonyl amino and C₁₋₆ alkylsulfonyl amino, (xvii) C₁₋₆alkylcarbonyl, (xviii) carboxyl, (xix) C₁₋₆ alkoxy-carbonyl, (xx)carbamoyl, (xxi) mono-C₁₋₆ alkyl-carbamoyl, (xxii) di-C₁₋₆alkyl-carbamoyl, (xxiii) C₆₋₁₀ aryl-carbamoyl, (xxiv) sulfo, (xxv) C₁₋₆alkyl sulfonyl, (xxvi) C₆₋₁₀ aryl and (xxvii) C₆₋₁₀ aryloxy; R² is ahydrogen atom; X is a methyne group which may be substituted; and a ringB is a homo- or hetero-cycle which may be substituted, or apharmaceutically acceptable salt thereof to a mammalian cell.
 16. Amethod as claimed in claim 15 wherein the ring A′ is a 3 to 10 memberedcyclic hydrocarbon.
 17. A method of claim 15 wherein the mammalian cellis in a mammal suffering from a nerve disease or bone/joint disease. 18.A method as in claim 17 wherein said mammal is suffering from a nervedisease selected from a group consisting of nerve degeneration as foundin cerebrovascular dementia, senile dementia, or Alzheimer's disease;amyotrophic lateral aclerosis; diabetic peripheral neuropathy; andParkinson's disease.
 19. The compound as claimed in claim 1, wherein thering A is a homo-cycle which is substituted by a C₁₋₆ alkylenedioxygroup.
 20. The compound as claimed in claim 1, wherein R¹ is (i) anamino group which may be substituted by (a) a hydrocarbon group whichmay be substituted, (b) a hydroxy group which may be substituted or (c)an acyl group or (ii) a nitrogen-containing heterocyclic group which hasa binding site on a ring-component nitrogen atom, optionally havingsubstituents.